Protein Tyrosine Phosphatase Variants in Human Hereditary Disorders and Disease Susceptibilities

Biochimica et Biophysica Acta 1832 (2013) 1673–1696

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Review Protein tyrosine phosphatase variants in human hereditary disorders and disease susceptibilities

Wiljan J.A.J. Hendriks a,⁎, Rafael Pulido b,c,⁎⁎ a Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands b BioCruces Health Research Institute, Barakaldo, Spain c IKERBASQUE, Basque Foundation for Science, Bilbao, Spain article info abstract

Article history: Reversible tyrosine phosphorylation of proteins is a key regulatory mechanism to steer normal develop- Received 19 March 2013 ment and physiological functioning of multicellular organisms. Phosphotyrosine dephosphorylation is Received in revised form 14 May 2013 exerted by members of the super-family of protein tyrosine phosphatase (PTP) enzymes and many play Accepted 16 May 2013 such essential roles that a wide variety of hereditary disorders and disease susceptibilities in man are Available online 23 May 2013 caused by PTP alleles. More than two decades of PTP research has resulted in a collection of PTP genetic variants with corresponding consequences at the molecular, cellular and physiological level. Here we present a Keywords: Cell signaling comprehensive overview of these PTP gene variants that have been linked to disease states in man. Al- Disease susceptibility though the ﬁndings have direct bearing for disease diagnostics and for research on disease etiology, more Phosphotyrosine dephosphorylation work is necessary to translate this into therapies that alleviate the burden of these hereditary disorders Post-translational modiﬁcation and disease susceptibilities in man. © 2013 The Authors. Published by Elsevier B.V. Open access under CC BY-NC-ND license.

1. Introduction organisms. It relies on the biochemically opposing actions of the protein kinase and protein phosphatase enzyme families. Phosphoryla- Reversible phosphorylation of proteins represents a key mecha- tion of tyrosine residues within proteins in order to steer cell nism in the control of cellular development and function in living decisions rapidly took center stage in the period that multicellularity evolved [1] and, accordingly, mutations in protein tyrosine kinase genes and the signaling pathways they control underlie growth defects and developmental disorders in man (e.g. [2]). It is therefore to be expected that enzymes of the super-family of protein tyrosine phosphatases (PTPs) are equally important to safeguard physiological processes, and indeed PTP gene inactivation studies in model organ- Abbreviations: AURKA, aurora kinase A; CAM, cell adhesion molecule; CD, Crohn's isms revealed developmental abnormalities for several representa- – – disease; CMT, Charcot Marie Tooth; DEP-1, Density-enhanced phosphatase-1; DUSP, fi fi dual-specificity PTP; EYA, eyes absent; FERM, Band 4.1/Ezrin/Radixin/Moesin; FNIII, fi- tives [3,4]. Some twenty- ve years ago the rst PTP sequences were bronectin type III; GLEPP1, glomerular epithelial protein 1; HPE, holoprosencephaly; unraveled, and the current list holds over a hundred distinct PTP HTT, hereditary haemorrhagic telangiectasia; Ig, immunoglobulin; IR, insulin receptor; genes within the human genome [5]. Research since then not only JMML, juvenile myelomonocytic leukemia; KIND, kinase non-catalytic C-lobe domain; firmly established their diverse roles in multicellular signaling path- MKP, MAP kinase phosphatase; MTMR, myotubularin-related protein; MS, multiple ways but also convincingly demonstrated PTP involvement in various sclerosis; NS, Noonan syndrome; PDZ, PSD95/Dlg/ZO-1; PHTS, PTEN hamartoma tumor syndromes; PI(3,4,5)P3, phosphatidylinositol 3,4,5-triphosphate; PRL, phospha- human disorders and disease susceptibilities [4,5]. Mutations and ex- tase of regenerating liver; PTEN, phosphatase and tensin homolog; PTP, protein tyro- pression alterations of PTP genes that occur in human somatic cells sine phosphatase; RA, rheumatoid arthritis; RLS, restless legs syndrome; RPTP, have been reviewed extensively over the past years [6–10]. Here, fi receptor-type PTP; RTK, receptor tyrosine kinase; SCID, severe combined immunode - we present a comprehensive overview of the current knowledge on ciency; SFK, Src-family tyrosine kinase; SH2, Src homology type 2; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; STEP, striatal-enriched PTP; PTPs that are implicated in hereditary human pathologies (Fig. 1). XLMTM, X-linked myotubular myopathy Main characteristics are compiled in Table 1. ⁎ Correspondence to: W.J.A.J. Hendriks, Department of Cell Biology, Nijmegen Centre We will first discuss class I cysteine-based non-transmembrane and for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Geert receptor-type PTP genes of the ‘classical’ phosphotyrosine-specificen- Grooteplein 28, 6525 GA Nijmegen, The Netherlands. Tel.: +31 24 3614329. zyme subfamily, before embarking on genes encoding so-called dual ⁎⁎ Correspondence to: R. Pulido, BioCruces Health Research Institute, Plaza de Cruces, fi s/n 48903 Barakaldo-Bilbao, Spain. speci city phosphatases (DUSPs). DUSP-type PTPs not only remove E-mail addresses: [email protected] (W.J.A.J. Hendriks), phosphate groups from phospho-tyrosines but many also catalyze the [email protected] (R. Pulido). dephosphorylation of phospho-threonine and phospho-serine residues

0925-4439 © 2013 The Authors. Published by Elsevier B.V. Open access under CC BY-NC-ND license. http://dx.doi.org/10.1016/j.bbadis.2013.05.022 1674 W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696

109 Protein Tyrosine Phosphatase Genes PTP

membrane Class I Cl. II Cl. III Cl. IV Cl. V anchor (35/99) (1/1) (1/3) (2/4) (2/2) SH2

KIND Classical, phosphotyrosine-specific PTPs Dual-specificity PTPs Lmw- cdc25 EYA TULA (22/38) (13/61) PTP FERM

PDZ non-transmembrane PTPs Receptor-type PTPs MKPs PTENs PRLs MTMRs Atypical (11/17) (11/21) (3/11) (1/5) (1/3) (7/16) (1/19) PEST

Pro-rich PTPN1 PTPN6 PTPN13PTPN14 PTPN12 PTPN5 PTPRA PTPRC PTPRD PTPRJ PTPRN2 PTPRZ1 DUSP1 PTEN PTP4A1 MTM1 EPM2AACP1 CDC25A EYA1 UBASH3A PTPN2 PTPN11 PTPN21 PTPN22 PTPN7 PTPRF PTPRO DUSP6 MTMR2 EYA4 UBASH3B PTPRR PTPRS PTPRQ DUSP9 MTMR3 KIM MTMR7 MTMR9 FNIII SBF2 MTMR14 Ig-like

N-term. 250 residues CAD CDC25 homology

C2 domain

pleckstrin homology carbohydrate- binding rhodanese homology N-terminal domain

UBA

C-term. SH3

Fig. 1. PTP gene family members that link to human disease predisposition. Shown are human gene names (on a pink background) and representative schematic domain depictions for PTPs that have been associated with hereditary disorders or disease susceptibilities. The main PTP classes and their subdivisions (yellow and orangebackground,respectively)according to Alonso et al. [11], with inclusion of the TULA family [19] as a ﬁfth class, are indicated. Note that CDC14 and slingshot type DUSP subfamilies (containing 4 and 3 genes, respectively) are not included because as yet no link to a hereditable human disease state has been described. Numbers between brackets reﬂect the number of disease-linked genes versus the total number of genes in that particular PTP (sub)class. The panel on the right provides a legend to the protein domains used in the schematic depictions of the PTPs in each subclass. The black double line that comes with the receptor-type PTP drawings symbolizes the cell membrane. Note that PTP catalytic domains are in pink and on the cytosolic side. Drawings are to scale and a size indication is included. See the text sections on the respective PTPs for detailed description and references.

in proteins, and some even take phospholipids, phosphorylated carbo- 2. Cys-based classical, non-transmembrane PTPs hydrates or oligonucleotides as substrates [11,12]. In the end we will discuss two out of the four aspartate-based ‘Eyes Absent’ PTP genes, 2.1. PTPN1 which encode enzymes that use an aspartic acid residue instead of the usual cysteine at their catalytic center. The gene PTPN1, encoding the paradigm protein tyrosine phos- For many of the PTP disease genes either loss-of-function or gain- phatase PTP1B that resides at the endoplasmic reticulum, is located of-function mutations have been documented, but for other PTPs thus in a genome region (20q13.1–q13.2) that represents a susceptibility far single nucleotide polymorphisms (SNPs) have been associated with locus for the development of insulin resistance in type 2 diabetes disease susceptibilities and mechanistic links remain to be elucidated mellitus [20]. This region spans some 20-odd genes, several of (Fig. 2). A depiction of putative mechanisms that connect some of the which have ties with insulin signaling and energy metabolism, and addressed PTPs with hereditary human disorders or disease susceptibili- evidence was provided for a direct role of PTP1B [21–26]. This is in ties is provided in Fig. 3. To our knowledge, no evidence exists yet on line with the finding that PTP1B dephosphorylates, hence inactivates, the involvement of the class III cysteine-based CDC25 PTPs in hereditary the insulin receptor and several downstream targets [27]. In the 3′ human disease, with the exception of the report of single nucleotide poly- untranslated region of the PTPN1 messenger a single nucleotide inser- morphisms(SNPs)attheCDC25A gene which confer a risk to develop tion was observed that was associated with features of insulin resis- breast cancer [13]. Also for the highly polymorphic gene ACP1,encoding tance in two different populations. Importantly, this insertion led to the class II cysteine-based LMW-PTP “redcellacidphosphatase”, allelic higher PTPN1 transcript levels in skeletal muscle due to an increase variants have been reported to associate with a variety of human diseases, in mRNA stability as compared to the wild-type transcript. Thus, the including diabetes, allergic and autoimmune inflammatory disorders, id- 1484insG allele causes PTP1B overexpression and contributes to the iopathic epilepsies, cancer, and vascular disease [14–18].Aboutadecade development of insulin resistance [21]. This is consistent with the ago a fifth PTP class, characterized by a histidine as the essential residue findings that PTP1B knockout mice exhibit increased sensitivity to in- in their active site, could be added to the superfamily (Fig. 1). The two dis- sulin and are resistant to high-fat diet-induced diabetes and obesity tinct genes, UBASH3A and UBASH3B, encode TULA-family proteins that [28,29], and that decrease of miRNA-122, which targets PTP1B down-regulate receptor-mediated signals in T-cells and platelets [19], mRNA, causes hepatic insulin resistance in mice [30]. Moreover, anti- and non-coding SNPs within the genes showed linkage to autoimmune sense oligonucleotides targeting PTP1B improve insulin sensitivity in disease susceptibility (Fig. 4). These association studies prompt for further rodent and monkey models [31,32], indicating that reducing PTP1B experiments to disclose whether and how the class II, III and V PTPs may levels could be an appropriate therapy for type 2 diabetes in humans influence the involved pathologies. (see below). W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 1675

Table 1 Properties of PTPs involved in hereditary human disorders and/or disease susceptibilities.a

Gene Phenotype in knock-out mouse models Hereditary human disorder/disease Mutation type—effect in disease (Chrom.loc) susceptibility Protein

Cys-based classical PTPs, non-receptor PTPN1 Increased insulin sensitivity Type 2 Diabetes Mellitus (T2DM) 3′UTR SNP—increased mRNA (20q13.1–13.2) Resistance to obesity Hypertension & related metabolic traits stability PTP1B (e.g. cholesterol levels) SNPs—hyperalleles? SNPs (incl. p.P387L)—? PTPN2 Growth retardation, thymic atrophy, defective Inflammatory Bowel Disease (incl. Upstream SNP—Decreased? (18p11.3–11.2) haematopoiesis and immune function, systemic Ulcerative Colitis, Crohn's disease) Intronic SNP—Decreased TCPTP inflammation, postpartum lethality Rheumatoid Arthritis, Type 1 Diabetes Mellitus (T1DM) PTPN5 Enhanced ERK1/2 phosphorylation in relevant Schizophrenia/Cognition disorders SNPs—Increased transcript levels (11p15.1) brain areas, improved cognitive performance, STEP reduced amnesic effects of alcohol PTPN6 me, mev: chronic inflammation, autoimmunity Neutrophilic Dermatoses SNP (p.E441G) & Del—reduced activity (12p12–13) meB2: autoinflammation similar to neutrophilic SHP1 dermatoses PTPN7 Enhanced ERK1/2 phosphorylation in T cells Height in infants SNP—? (1q32.1) HePTP PTPN11 Early embryonic lethal, survival signaling defects Noonan Syndrome Gain-of-function (12q24) Leopard Syndrome Loss-of-function SHP2 Juvenile Myelomonocytic Leukemia Gain-of-function Metachondromatosis Loss-of-function Tetralogy of Fallot, T1DM, Systemic Intronic SNP—? Lupus Erythematosus (SLE) PTPN12 Embryonic lethal Risk for breast cancer SNP—reduced activity (7q11.23) PTP-PEST PTPN13 Reduced nerve repair Familial hepatocellular carcinoma SNP—reduced activity (4q21.3) Improved host defense against intrapulmonary K. Risk for NHSCC, lung carcinoma, and co- SNPs—altered activity PTPN13 pneumoniae lorectal cancer PTPN14 Limb swelling Congenital Lymphedema Del—Loss-of-function (1q32.2) Periorbital edema Haemorrhagic Telangiectasia SNP—? Pez Lymphatic capillary hyperplasia PTPN21 No reports Schizophrenia SNPs (p.V936A, p.L385F)—? (14q31.3) PTPD1 PTPN22 Effector/memory T-cell expansion resulting in T1DM, Rheumatoid Arthritis, Hashimoto SNP—p.R620W risk allele (1p13.2) splenomegaly and lymphadenopathy upon ageing Thyroiditis, Graves Thyroiditis, SLE, SNP—p.R263Q protective effect Lyp Altered regulatory T cell levels in thymus Familial Hypoadrenocorticism/Addison's Disease, Psoriasis, ANCA Systemic Lupus Erythematosus

Cys-based classical PTPs, receptor PTPRA Neurodevelopmental and peripheral myelination Schizophrenia Intronic SNP—Altered isoform ratio? (20p13) defects RPTPα Impairments in synaptic plasticity and short-term memory PTPRC No T cells, impaired positive and negative selection Severe Combined Immunodeficiency Loss-of-function (1q31–q32) of B-cells Multiple Sclerosis 77G SNP—isoform switch, increased CD45 Myelination defects Hepatitis C Virus Susceptibility activity Rheumatoid Arthritis 77C SNP—isoform switch, reduced activity SNP—? PTPRD Growth retardation, posture and motor defects, Restless Legs Syndrome 5′UTR SNPs—RNA production/ (9p24.3–p23) RPTPδ impaired learning and memory, early mortality Clear cell Renal Cancer stability ? 5′UTR SNP—Reduced expression PTPRF Defects on mammary gland development and milk Syndromic amastia Translocation—Protein absence (1p34) production T2DM and related coronary artery Intronic SNP—? LAR Decreased size and number of basal forebrain disease cholinergic neurons Spatial learning impairment PTPRJ SFK-mediated regulatory function in B cells and Early-onset Familial Colorectal Cancer Micro-duplication—Epigenetic (11p11.2) macrophages Risk for breast cancer, papillary thyroid silencing DEP-1 Platelet phenotype: bleeding tendency, defective carcinoma, head and neck squamous cell SNPs—? arterial thrombosis carcinoma, lung carcinoma SNPs—Loss-of-function? Heparin-induced thrombocytopenia PTPRN2 Reduced glucose-stimulated insulin release Co-morbid Cocaine Dependence and SNP—? (7q36) Major Depressive Episode CNV—? Phogrin Attention Deficit Hyperactivity Disorder PTPRO Podocyte abnormalities, hypertension, reduced Idiopathic Nephrotic Syndrome Splice mutant—loss of function (12p12.3) glomerular filtration Neurocognitive diseases Intronic SNPs—? GLEPP1 Abnormal DRG development, perturbed nociception and proprioception

(continued on next page) 1676 W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696

Table 1 (continued) Gene Phenotype in knock-out mouse models Hereditary human disorder/disease Mutation type—effect in disease (Chrom.loc) susceptibility Protein

PTPRQ Auditory hair bundle defects, defective vestibular Autosomal Recessive Nonsyndromic Loss-of-function (12q21.2) hair cells Hearing Loss 84 (DFNB84) PTPRQ PTPRR Elevated MAPK phospho-levels in speciﬁc brain Major Depressive Disorder intronic SNP—gain-of-function? (12q15) areas, impaired locomotion and balancing skills PCPTP1 PTPRS Reduced brain size, abnormalities in pituitary and T2DM SNPs—? (19p13.3) olfactory lobes Ulcerative Colitis intronic SNPs—inﬂuence splicing RPTPσ Improved nerve regeneration (exon skipping) Altered glucose homeostasis, Ulcerative colitis PTPRZ1 Defects in remyelination Schizophrenia SNPs—increased expression (7q31.3) Learning impairment RPTPζ Decreased B-cell survival

Cys-based DUSP PTPs DUSP1 Enhanced innate immunity Clinical response to inhaled SNPs—increased levels? (5q34) Inflammatory bone loss corticosteroid therapy in asthma patients MKP1 Sensitivity to collagen II-induced arthritis Exacerbation of colitis in IL-10 deficient mice Increased acetaminophen-induced hepatic injury Defective skeletal muscle regeneration Resistance to diet-induced obesity Protection against atherosclerosis in ApoE-null mice DUSP6 Dwarfism-related skeletal abnormalities and Bipolar Disorder SNPs (p.L114V, p.S144A)—hyperactivity? (12q22–23) deafness MKP3 Cardiac hypercellularity PTEN PTEN null mice: embryonic death at day 8 PTEN Hamartoma Tumor Syndrome Loss-of-function mutations (10q23.3) Heterozygous mice: highly susceptible to tumor Macrocephaly/Autism Syndrome Loss-of-function mutations PTEN formation Atherosclerotic cerebral infarction SNPs—? Chronic obstructive pulmonary disease SNPs—? PTP4A1 No reports Alcohol Dependence SNPs—? (6q12) PRL-1 MTM1 (Xq28) Muscle atrophy, respiratory disfunction, die within X-linked Myotubular Myopathy Loss-of-function mutations MTM1 2 months MTMR2 myelin outfoldings, specifically in Schwann cells, Charcot–Marie–Tooth disease 4B1 Loss-of-function mutations (11q22) impaired nerve conduction MTMR2 MTMR3 No reports Susceptibility to lung and gastric cancer, SNPs—decreased mRNA levels? (22q12.2) and to childhood onset inflammatory MTMR3 bowel disease MTMR7 No reports Risk to variant Creutzfeldt-Jakob SNP—? (8p22) MTMR7 MTMR9 No reports Susceptibility to metabolic syndrome SNP—? (8p23-p22) and obesity MTMR9 SBF2 nerve conduction defects and abnormal myelin Charcot-Marie-Tooth disease 4B2 Loss-of-function mutations (11p15.4) folding Stature SNP—? MTMR13 MTMR14 skeletal muscle phenotype: fatigue, reduced Autosomal Centronuclear Myopathy Loss-of-function mutations (3p25.3) tolerance to exercise, abnormal T-tubule morphol- MTMR14 ogy, increased autophagy EPM2A Neuronal degeneration, Lafora inclusion body Myoclonic Epilepsy of Lafora Loss-of-function mutations (6q24) formation resulting in impaired behavioral Laforin responses, ataxia and seizures

Asp-based PTPs EYA1 Defects in development of multiple organs, Branchio-Oto-Renal Syndrome 1 Loss-of-function mutations (8q13.3) respiratory failure at birth Oto-facio-cervical Syndrome Large deletions (ﬂanking genes) EYA1 Vesico-ureteral reﬂux SNP—trend only EYA4 Defects in eustachian tube and middle ear Autosomal Dominant Deafness 10 Loss-of-function (6q23) Dilated Cardiomyopathy Additional Loss-of-function EYA4 Holoprosencephaly Large deletion Anti-TNF therapy responsiveness in RA Intronic SNP—?

?: The effect of the SNP on PTP transcript levels or protein activities is currently unknown. a See the text sections on the respective PTPs for detailed description and references.

A rare PTP1B missense mutant (P387L) was found associated with serine residue in PTP1B but it remains to be demonstrated whether the increased risk for type 2 diabetes in the Danish Caucasian population unphosphorylated variant has a higher enzymatic activity. In a local [23]. This mutation hampers the phosphorylation of a nearby conserved subarctic community in central Canada a SNP in PTPN1 exon 8 was W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 1677

Mutations linked to disease Effect of mutation/ Effect of SNP: PTPN12 PTPN2 PTPRA PTPN11 gain of function PTPN6 PTPRD PTPN11 PTPN7 PTPRR PTPN14 loss of function unknown PTPN1 PTPN13 PTPRS PTPRC PTPN5 PTPN21 PTPRZ1 PTPRF PTPRJ PTPN22 Substrate type: PTPRO DUSP6 DUSP1 EYA1 proteinaceous

PTPRN2 PTEN MTM1 PTPRQ non-proteinaceous MTMR2 MTMR14 EPM2A

PTP4A1 EYA4 SBF2* unknown

SNPs associated with disease susceptibility

Fig. 2. Venn diagram showing the distribution of PTP gene variants with respect to disease-causing mutations (reddish purple square) or modifiers of disease susceptibility (green square on the left). Gene name colors symbolize the mutation's effect on enzyme activity, and vertical segmentation by the dashed lines reflects the substrate preference of the PTPs involved, as indicated in the rightmost (grey) panel. Asterisk indicates a myotubularin-type PTP that lacks enzymatic activity. See the text sections on the respective PTPs for detailed description and references. found associated with reduced risk for either impaired glucose toler- reasons of completeness, it should be noted that the associations of ance or type 2 diabetes [22]. This SNP is silent at the amino acid level, PTPN1 SNPs with type 2 diabetes could not be replicated in some co- however, and therefore does not add to mechanistically defining a pro- horts (e.g. [33,34]). tective role for PTP1B. Bowden and coworkers used a comprehensive In a recent study that exploited rare SNPs within the PTPN1 gene set of SNPs covering the PTPN1 genomic region and found that all region a contribution of PTP1B to the pathogenesis of hypertension, SNPs within the PTPN1 transcription unit significantly associated with i.e. dyslipidemia and obesity, was noted in Chinese subjects [35]. type 2 diabetes, insulin sensitivity and fasting glucose levels but only Also a study in the Dutch Caucasian population revealed PTPN1 two (including 1484insG) did so with acute insulin responsiveness in SNPs to be associated with total plasma and LDL cholesterol levels the Caucasian population [24,26]. It is tempting to speculate that the [36]. Both studies in fact corroborate earlier findings on the genetic non-coding SNPs have bearing for the corresponding PTPN1 transcript basis of hypertension [37] that linked PTP1B to the regulation of plas- levels in insulin-responsive tissues, but this awaits assessment. For ma lipid levels, hence to obesity and hypertension. A polymorphism

PTPRN2 PTPN5 DUSP6 PTPN21 PTPRA PTPRZ1 PTPN2 PTPN6 PTPN22 PTPRC DUSP1 PTPRR Fyn Src Src, JAKs Lck, Syk, ZAP70 Lck SFKs JNK, p38

Secretory Glu-receptor ERK1/2 Defective High levels of inflammatory cytokines vesicle release internalization hypoactivation myelination

Mood disorders Inflammatory diseases

PTPN11 PTPN13 PTPRD PTPRJ PTEN PTPN1 PTPRS PTPRF

Ras SFKs, SFKs, STAT3 ERK RTKs AURKARTKs PI(3,4,5)P3 JAKs, IR

Proliferation, transformation, pro-survival Defective insulin signaling

Cancer predisposition Type 2 diabetes

Fig. 3. Possible mechanisms involving selected PTPs in human hereditary mood disorders (top left), inﬂammatory diseases (top right), cancer susceptibility (lower left) and type 2 diabetes mellitus (lower right). The mechanistic insights usually are based on a combination of phenotypic characterization of mutant mouse models, genotype-phenotype correlations coming from patient data, and functional tests at the molecular level in appropriate cell models. Color codes for PTPs are as in Fig. 2: vermillion, gain-of-function; blue, loss-of-function; black, unknown. Arrows, positive effect; blunted arrows, negative effect; dotted arrows, indirect effect. See the text sections on the respective PTPs for detailed description and references. 1678 W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696

Local Mental disorders PTPN5, PTPN21, PTPRA, PTPRN2, PTPRO, PTPRR, PTPRZ1, DUSP6, PTEN, PTP4A1

Neurodegeneration MTMR7, EPM2A

Deafness PTPRQ, EYA4

Airway infections DUSP1

Amastia PTPRF

Renal diseases PTPRO

Vascular abnormalities PTPN14, ACP1

Neuromuscular diseases MTM1, MTMR2, SBF2, MTMR14

Restless Legs Syndrome PTPRD

Skin diseases* PTPN6

Systemic Malformation syndromes PTEN, EYA1, EYA4 Autoimmune diseases PTPN2, PTPN11, PTPN22, PTPRC, MTMR3, ACP1, UBASH3A, UBASH3B

Immune deficiencies PTPRC

Type 2 Diabetes PTPN1, PTPRF, PTPRS, DUSP9

Metabolic disorders PTPN1, MTMR9

Cancer susceptibility PTPN11, PTPN12, PTPN13, PTPRD, PTPRJ, PTEN, MTMR3, ACP1, CDC25A

(trait) Height PTPN7, SBF2

Fig. 4. PTP hereditary disease genes grouped according to their local (top) or more systemic (bottom) phenotypic effects. See the text sections on the respective PTPs for detailed description and references. Asterisk; note that dermatoses related to PTPN6 variants reflect an inflammatory disease due to neutrophil dysfunction. in PTPN1 intron 6 was also shown to impact on body fat distribution and development and on overall survival are greatly influenced by the ge- type 2 diabetes risk [25].Inthatstudy[25] also the association of the netic background of the mice [46]. PTPN1 P387L mutation with lower glucose tolerance was confirmed. As of the molecular mechanism, a recent study revealed that a Taken together, although type 2 diabetes and obesity are clearly disease-associated, intronic variant of PTPN2 led to decreased TCPTP ex- multifactorial diseases and PTP1B protein activity studies in patient pression (as compared to the normal allele) in T cells, and negatively im- samples are lacking, the mounting evidence that PTP1B activity is a de- pacted on the IL-2 and IL-15 responsiveness of these cells [47].The termining factor in these diseases warrants the further quest for phar- authors speculate that reduced TCPTP levels indirectly lead to enhanced macologically effective inhibitors to conquer these major disease activity of potential inhibitors of IL-2Rβ signaling, thereby regulating cyto- states (Figs. 3–4). kine responsiveness and autoimmune susceptibility. Studies in mice revealed that TCPTP-deficient CD8+ T cells alone are sufficient to transfer 2.2. PTPN2 inflammation and autoimmunity to wild-type recipient animals [48]. Subsequent experiments demonstrated that, by dephosphorylating and PTPN2 is closely related to PTPN1 and encodes TCPTP, an intracellu- inactivating Src family kinases (SFKs), TCPTP normally blunts antigen- lar PTP that comes in two flavors: a cytosolic variant and a nuclear induced T cell activation and proliferation [48], indicating that PTPN2 dis- splice-isoform [38,39]. The detection of PTPN2 focal deletions in a subset ease alleles thus cause a lowering of in vivo thresholds for TCR-dependent of human T-cell acute lymphoblastic leukemias illustrated its tumor responses. suppressive effect in lymphoid cells [40]. PTPN2 role in immune regula- But TCPTP's relevance for chronic inflammatory disorders may well tion is reflected by its identification as a susceptibility locus for autoim- extend beyond T cell functioning, as put forward by recent work on mune diseases, including Crohn's disease (CD), rheumatoid arthritis human intestinal cells that were obtained from CD patients or healthy (RA) and type 1 diabetes [20,41]. This is substantiated by multiple re- controls [49]. Earlier work had shown that the autophagy gene cent findings, including a confirmatory study under Spanish subjects ATG16L1 is associated with chronic inflammatory disorders, and this [42]. Genetic association studies in large cohorts of inflammatory prompted the investigators to monitor presence of CD-associated bowel disease patients has ultimately, by means of a meta-analysis of PTPN2 or ATG16L1 variants and the process of autophagosome forma- data from multiple independent studies, provided a significant association in the specimens. Collectively, their results now suggest a model tion with a SNP at the PTPN2 locus, some 5 kbp upstream of the tran- in which cytokines—in an mTOR/ATG16L1-dependent way—induce scription unit [43,44].Inflammatory bowel disease represents a TCPTP activity in the intestinal cells, thereby triggering a negative feed- genetically heterogeneous collection of pathologies, including CD and back loop on EGFR-mediated mTOR activity and promoting autophagy. ulcerative colitis. Further work should unravel which of the PTPN2 char- Reduced TCPTP levels thus boost mTOR activation and impair autopha- acteristics are altered in the SNP-associated allele as compared to wild gy, which leads to increased infection burden and elevated apoptosis of type but, in view of the impact of the associated protein on immune intestinal epithelial cells [49]. cell signaling [45], this points into the direction of reduced levels and PTPN1 and PTPN2 are two highly related genes, coding for proteins functionality. Indeed, TCPTP deficiency in mice results in reduced with an amino acid identity of 73% at their PTP domain. This makes a growth and systemic inflammation, culminating in lethality around specific interference with the catalytic activity of PTP1B or TCPTP, one month of age. Importantly, these effects on myeloid and bone which could be beneficial in therapies against type 2 diabetes and W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 1679 obesity (PTP1B inhibition-based therapy) or against inflammatory the SHP1 catalytic domain and a 1.7-kbp deletion that altered PTPN6 diseases (TCPTP activation-based therapy), extremely challenging. expression could account for disease development, but all other Alternative mechanisms to interfere with PTP1B or TCPTP function- cases revealed no mutations in PTPN6 gene sequences. Sharply con- ing, including specific regulation of protein levels, subcellular loca- trasting with healthy control material, however, all these patient tion, or targeting to substrates, need to be considered. samples displayed next to the full-length SHP1 mRNA an abundance of PTPN6 splice variants that likely encode nonfunctional protein 2.3. PTPN5 [61]. Given that also SHP1 phosphatase activity was found reduced in leukocytes of neutrophilic dermatoses patients, and that a sponta- The brain-specific phosphatase termed STEP (Striatal-enriched pro- neous insertional mutation in mouse Ptpn6 renders a neutrophilic tein tyrosine phosphatase) is encoded by gene PTPN5 and regulates syn- dermatosis phenotype [62], it is warranted to conclude that reduced aptic plasticity and neuronal function in the central nervous system SHP1 activity provides the molecular explanation of the pyoderma through dephosphorylation of key target molecules including MAP gangrenosum and Sweet's syndrome phenotypes. In the majority of kinases, SFKs and NMDA and AMPA receptor subunits [50].STEP- cases, however, the disease genes involved will rather function in mediated dephosphorylation inactivates the SFK targets but for the PTPN6 transcript processing. NMDA and AMPA receptor complexes this triggers their endocytosis. Ptpn5 knock-out mice have a normal brain morphology but increased 2.5. PTPN7 levels of MAP kinase phosphorylation in specific brain areas, improved hippocampal-dependent learning and memory, and a more dominant be- HePTP is a hematopoietic enzyme encoded by the PTPN7 gene and, havior were noted [51,52]. Evidence is accumulating that dysregulation of like PTPN5-encoded STEP, HePTP contains a so-called kinase interaction STEP also contributes to the pathophysiology of several neuropsychiatric motif that determines its binding to and dephosphorylation of MAP ki- disorders in man [53]. Schizophrenia affects 1% of the world population nases [63]. In doing so, HePTP could potentially block TCR-induced signal and is characterized by altered synaptic transmission, a decrease in transduction. However, Ptpn7 knock-out mice display no phenotypic white matter, and hypomyelination [54,55]. The disease is highly herita- consequences whatsoever and only in vitro a mild enhancement of ble, and the list of candidate genes that display linkage includes multiple MAPK activation following TCR stimulation was noted [64]. This points genes important for myelination and oligodendrocyte development. A ge- to efficient compensatory mechanisms in mouse and makes it hard to netic association of PTPN5 with schizophrenia and cognitive performance explain how a SNP analysis in Vietnamese-Korean families could point was recently discovered in a Jewish population using SNP haplotypes that to human PTPN7 as a genetic factor associated with height during early reside within the PTPN5 gene [56]. Moreover, preliminary data suggest childhood [65]. Clearly, the proposed link is in need of replication in ad- that these disease-associated alleles result in higher STEP transcript levels ditional cohorts. [56].Combinedwithpreviousfindings that glutamate receptor internalization contributes to the pathogenesis of schizophrenia, that elevated 2.6. PTPN11 STEP levels are found in the prefrontal cortex of Alzheimer's patients, and that reduction of STEP levels in mice improves cognitive performance PTPN11 encodes SHP2, a close homolog of SHP1 and also having two [53], this yields the picture that aberrancies in STEP activity levels contrib- SH2 domains. Many acquired and hereditary disease phenotypes are at- ute to neuropathologies. STEP-specific inhibitors that are able to pass the tributable to this protein [66–69]. Intriguingly, since both PTPN11 blood–brain-barrier would therefore be appealing drugs to treat a subset loss-of-function and gain-of-function mutations are incompatible with of psychiatric disorders and related cognitive defects. healthy life [70], this exemplifies how important exact fine-tuning in reversible phospho-tyrosine-mediated signaling in fact is. Many receptor- 2.4. PTPN6 type molecules, including growth factor and cytokine receptors, act upstream of SHP2 and regulate the balance between its open (active) and Genes PTPN6 and PTPN11 both encode tyrosine-specific phospha- closed (inactive) conformation [71]. Once activated, its primary targets tases that harbor tandem N-terminal Src homology type 2 (SH2) do- reside in the Ras-ERK MAP kinase and Jak-STAT signaling pathways mains. These PTPs exist in a closed, inactive conformation in which [67]. SHP2 hyperactivity causes Noonan syndrome (NS), an autosomal the N-terminal SH2 domain prevents access to the catalytic domain. Ac- dominant dysmorphic syndrome that has an estimated incidence of 1 tivation requires that this N-terminal SH2 domain starts binding in 1000 to 2500 newborns [69]. It is characterized by hypertelorism, phospho-tyrosine residues in other proteins, thereby opening up the downward eyeslant, low-set posteriorly rotated ears, and also short stat- catalytic domain in the PTP [57]. Naturally occurring mouse mutants ure, webbed neck, cardiac anomalies, epicanthic folds, deafness, motor that suffer from complete or partial inactivation of the Ptpn6 gene, des- delay and bleeding diathesis have been observed. Moreover, an in- ignated “motheaten” and “motheaten viable”, respectively, have pro- creased risk for hematological malignancies and other cancers has been vided insight into the biological function of the Ptpn6-encoded found for NS patients [72,73]. Decreased catalytic activity of SHP2, on protein, SHP1 [58]. The homozygous mutant mice suffer from chronic the contrary associates with LEOPARD syndrome, a genetically heteroge- inflammation and autoimmunity and their lifespan is considerably re- nous disorder that manifests with multiple lentigines, cardiac conduc- duced. Heterozygous animals develop lymphoma and leukemia at tion abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal higher age. Collectively the data show that SHP1 functions as an impor- genitalia, retardation of growth, and sensorineural deafness. The partial tant regulator of the myelopoietic system [59]. Of course this is exerted overlap in phenotypic consequences observed for these two syndromes by dephosphorylating key substrates, which include multiple RTKs [60]. [66] suggests that SHP2 hypo- and hyper-activity affect developmental Motheaten mice display focal skin inflammations and patchy ab- pathways in a similar manner [70]. SHP2 NS mutations mainly disrupt sence of hair, due to increased numbers of neutrophils in the subder- the inhibitory interaction between the N-terminal SH2 and the catalytic mal tissue [58]. Similar pathologies—i.e. extensive skin infiltration by domain; on the other hand, SHP2 LEOPARD syndrome mutations mainly neutrophils—are present in humans that suffer from pyoderma reside in the catalytic domain, reducing catalytic activity but increasing gangrenosum and Sweet's syndrome, but the genetic causes of these binding to upstream activators and scaffolding adapters [74,75]. two uncommon neutrophilic dermatoses that are associated with he- Ras-ERK MAP kinase signaling is a key pathway downstream of mutant matological tumors are currently not known. It will therefore come as SHP2 (Fig. 3) which is further substantiated by the discovery of activat- no surprise that patients with idiopathic neutrophilic dermatoses ing mutations in other factors of the pathway in NS and LEOPARD were recently investigated for potential PTPN6 abnormalities [61].In syndrome patients [69]. Moreover, the mutation spectrum that is one patient indeed a combined heterozygous mutation (E441G) in found in the juvenile myelomonocytic leukemia (JMML) and associated 1680 W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 myelodisplastic disorders mainly consists of mutations in PTPN11 [76],as kinase non-catalytic C-lobe domain) domain, a FERM (acronym for well as germline NRAS, KRAS2, NF1 and ARHGAP26 mutations that result Band 4.1, Ezrin, Radixin, Moesin) domain and five PDZ (PSD95, Dlg, in enhanced Ras-MAPK signaling [66–69]. The examples of mutational ZO-1) domains in addition to its single, C-terminal catalytic PTP domain overlapping between NS and JMML are rare, and it has been proposed [87]. This impressive and unique repertoire of anchoring and scaffolding that isolated NS germline PTPN11 mutations have milder gain-of- domains suggested an important role for PTPN13 in submembranous function phenotypes than mutations from isolated JMML and other signaling events but remarkably the phenotypes of Ptpn13 mutant pediatric myelodisplastic disorders [74]. In addition, STAT3 function mice appeared extremely subtle [88,89]. The 4q region is often found downstream of SHP2 is also involved in NS phenotype (Fig. 3). The hema- deleted in hepatocellular carcinomas and this prompted investigations topoietic phenotype of STAT3 deficient mice shows high autonomous towards a possible involvement of PTPN13 in tumorigenesis. Multiple myeloid cell proliferation which resembles the phenotype of mice reports on somatic PTPN13 mutations in cancer specimens penetrated carrying a knock-in hyperactive SHP2 mutant [77]. SHP2-mediated de- the literature [90,91] and, additionally, several PTPN13 polymorphic al- phosphorylation and inactivation of STAT3 thus contributes to the patho- leles were found to increase the risk of developing multiplex familial genesis of NS and JMLL [78]. hepatocellular carcinoma [92], head and neck squamous cell carcinoma Recently, a new Mendelian disease was added to the PTPN11 track re- [93], or lung and colorectal cancer [94]. A few such polymorphic PTPN13 cord. Next generation sequencing technology allowed the analysis of the variants have been investigated at the protein level and were found to full genome of a single patient with the autosomal dominant incom- reduce the binding capacity of PTPN13's second PDZ domain [92],ap- pletely penetrant combined exostosis and enchondromatosis tumor syn- parently contrasting with the effects of somatic PTPN13 mutations in drome termed metachondromatosis [79]. A deletion in PTPN11 exon four cancer specimens that rather result in the loss of catalytic PTP activity that co-segregated with the phenotype and that alters the SHP2 reading [95,96]. The advent of next generation sequencing techniques will un- frame causing a premature stop was found. The results could be con- doubtedly further fill the catalog of disease-related PTPN13 variants, firmed in a second affected family that displayed a nonsense mutation and it will be insightful to document whether these impinge on the in PTPN11 exon 4 [79]. In an independent study, also classical linkage protein's interaction domains or rather its catalytic C-terminal end. analysis using SNP arrays and ultimately targeted sequence analysis led to the identification of PTPN11 loss-of-function mutations in about half of the investigated metachondromatosis families [80]. Importantly, in 2.9. PTPN14 microdissected lesions from patients loss-of-heterozygosity for the wild-type allele could be demonstrated, underscoring the tumor sup- The PTPN14-encoded protein Pez also combines a membrane- pressive nature of SHP2 activity in the affected cell types [80].Inthere- associating FERM domain with a PTP catalytic segment but as compared lated multiple enchondromatosis disorders Ollier disease and Maffucci to PTPN13 it lacks KIND and PDZ domains. In a consanguineous Yemenite syndrome no loss-of-function mutations in PTPN11 could be detected. family, a homozygous 2 kbp deletion within the PTPN14 gene has been Lastly, an association study for common genetic variants of 22 can- found in affected individuals with autosomal-recessive lymphedema- didate genes underlying tetralogy of Fallot, a congenital heart defect choanal atresia syndrome [97]. The concomitant loss of PTPN14 exon 7 that often presents in the context of multisystemic diseases like causes a frameshift, resulting in a prematurely truncated, instable Pez Down syndrome and Holt-Oram syndrome, revealed a single SNP at protein that spans until halfway its FERM domain and lacks catalytic ac- the PTPN11 locus in a British cohort [81]. Intriguingly, the PTPN11 tivity. To substantiate the findings a gene-trap mouse model was gener- SNP that was found associated with tetralogy of Fallot is in intron 6 ated that indeed partially recapitulated the disease phenotype [97]. and has also been linked with autoimmune disorders like type 1 dia- Although animals did not develop choanal atresia, a considerable num- betes and systemic lupus erythematosus (SLE). It is as yet unclear ber had swelling of the limbs or periorbital edema and showed hyperpla- whether it is causing altered PTPN11 expression or rather acts on sia of lymphatic ear capillaries. This puts forward Pez as a unique other, neighboring genes that are involved in T-cell signaling. regulator of lymphatic and choanal development. With respect to the molecular mechanism, Pez was proposed to function in complex with 2.7. PTPN12 vascularendothelialgrowthfactorreceptor3,anRTKessentialfor lymphangiogenesis [97]. An alternative working scheme results from PTPN12 encodes PTP-PEST, a ubiquitous protein with abundance in studies that implicate polymorphic variants of PTPN14 in the modulation hemopoietic and epithelial cells that contains a long C-terminal domain of the severity of hereditary haemorrhagic telangiectasia (HTT), an with several proline-rich and PEST motifs. In the immune system, angiogenesis-related vascular dysplasia syndrome [98].Inthatstudya PTP-PEST negatively regulates TCR and BCR signaling [82]. By virtue of functional link of Pez with EphrinB2 or with activin receptor-like kinase its association to or dephosphorylation of adapter, signaling and cyto- 1 was proposed. But perhaps a refinement of the above molecular sce- skeletal proteins, PTP-PEST is also a major regulator of cell adhesion, narios seems appropriate now that recently Drosophila Pez turned out motility and migration [83]. Both tumor suppressive and oncogenic a positive regulator of the Hippo-Warts signaling cascade, which restricts properties have been assigned to PTP-PEST in human breast cancer. A fly intestinal stem cell proliferation [99].AlsoPTPN14 is an important tumor promoting mode of action was based on the finding that player in mammalian Hippo signaling [100–102]. PTP-PEST protected cells against aberrant ROS accumulation and oxidative stress-induced death [84]. In support of the opposite scenario is the finding that a T573A SNP in PTPN12, that resulted in a partial 2.10. PTPN21 loss-of-function variant when tested for capacity to suppress transformation in PTPN12-depleted cells, is enriched in breast cancer patients The protein PTPD1, encoded by gene PTPN21,ishighlyhomolo- as compared to healthy controls [85]. Oddly enough, the T573A variant gous to Pez but as yet it remains to be determined whether it also rather displayed increased phosphatase activity when tested in vitro is involved in mammalian Hippo signaling. Gene PTPN21 has been as- [86]. Additional studies may add up to a more decisive picture on the sociated with schizophrenia [103]. Mining of genome wide associa- role of PTP-PEST in breast cancer. tion datasets revealed two non-synonymous sequence variations in PTPN21 that independently represent significant risk alleles for 2.8. PTPN13 schizophrenia; p.L385P and p.V936A [103]. How one should envis- age the contribution of these alterations in size and hydrophobicity Gene PTPN13 resides at chromosome 4q21.3 and it encodes the larg- of the involved PTPD1 residues to schizophrenia etiology remains a est human non-transmembrane PTP; it consists of a KIND (putative future challenge. W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 1681

2.11. PTPN22 protein levels [118], and this may explain why the R620W allele associates with autoimmune diseases that have a strong autoantibody com- PTPN22 encodes three splice forms of the cytosolic PTP Lyp, also ponent (e.g. SLE, RA) and has no or even a protective effect in others named PEP, of which the longest isoform of 807 amino acids is the without dominant autoantibodies (e.g. CD). most abundant and hence best studied. PTPN22 is expressed exclusively but differentially in haematopoietic cells; Natural Killer cells and neu- 3. Cys-based classical, receptor-type PTPs trophils express highest levels while CD4+ T cells and monocytes express the lowest [104]. A genetic association between type 1 diabetes 3.1. PTPRA and a SNP in the coding region of PTPN22 was reported that corresponds to the so-called R620W amino acid substitution in a polyproline motif RPTPα, the product of the PTPRA gene is a receptor-type PTP (RPTP) within Lyp that may be involved in SH3 domain-mediated protein in- that is highly expressed in the developing and adult central nervous sys- teractions [105]. Following this discovery, several reports confirmed tem in both glial cells and neurons. RPTPα is comprised of tandem intra- the link to type 1 diabetes for R620W and in fact expanded its clinical cellular phosphatase domains, but only a short, heavily glycosylated reach to many other autoimmune diseases, including RA, SLE, myasthe- extracellular portion. RPTPα is the signaling subunit of co-receptor com- nia gravis, Hashimoto thyroiditis, and Addison disease [106,107].An- plexes with the cell adhesion molecules CNTN-1 and -6 as well as CHL1 other PTPN22 SNP variant, R263Q, has been associated with psoriasis and NCAM [119–122],wherebyRPTPα transduces positive signals in risk [108]. Interestingly, a massive genotyping study amongst several SFK signaling pathways modulating both cell interactions and synaptic thousand ulcerative colitis and CD patients and healthy controls re- plasticity [123,124].PolymorphismsinthehumanPTPRA locus (notably vealed that the R620W and R263Q polymorphisms in Lyp show differ- rs1016753) have been linked to schizophrenia, and post-mortem studies ential association in these patient groups: R263Q predisposes to on humans suffering from schizophrenia show decreased PTPRA tran- ulcerative colitis, whereas R620W was only significantly associated script in the dorsolateral prefrontal cortex [125]. In line with this, with CD [109]. Likewise, only R620W and not the novel R263Q was RPTPα knockout mice exhibit decreased expression of multiple genes in- found to influence systemic sclerosis genetic susceptibility [110].Final- volved in myelination, and show deficits in spatial learning and de- ly, both R620W and R263Q variants have been associated with pulmo- creased locomotor activity and anxiety, possibly reflecting symptoms nary tuberculosis [111]. of schizophrenia [125,126]. A candidate effector of these phenotypes is The arginine to tryptophan mutation is autosomal dominant, with in- Fyn, a SFK dephosphorylated and activated by RPTPα. Fyn knockout creased clinical penetrance in homozygous carriers. Whether R620W mice as well as catalytically inactive Fyn knock-in mice display a severe represents a gain- or loss-of-function variant is still debated and it may myelin deficit [127], and pharmacological inhibition of Fyn decreased even turn out that perhaps both gain- and loss-of-function is at stake. the accumulation of myelin proteins [128]. The findings in Ptpn22 knockout mice underscore a role for Lyp in negatively regulating SFK-mediated T cell receptor signaling but conversely 3.2. PTPRC the relatively mild loss-of-function phenotype in mice [112] may be taken as evidence that the human R620W variant represents a The CD45 protein isoforms that are encoded by gene PTPRC already gain-of-function mutant. Mechanistically, thoughts concentrate on the served as well-established cell surface markers in the hematopoietic importance of the polyproline motif in mediating an interaction with compartment long before the proteins were recognized as PTPs. It re- Csk, on direct effects on Lyp catalytic activity and protein stability. The quired the first phospho-tyrosine phosphatase sequence (of PTP1B) to Lyp–Csk complex is able to synergistically down-regulate the cytoplas- disclose that CD45's tandem cytoplasmic domains represent PTP moie- mic SFKs Lck and Fyn that are instrumental in T cell receptor signal ties, making CD45 the founding member of the transmembrane PTP propagation. Thus, since R620W impairs Lyp–Csk complex formation subclass [129,130]. Experiments in mice provided proof that the Ptprc [105], hyper-reactivity of T cells against autoantigens may explain gene encodes important regulators of immune cell function [131,132] autoinflammatory effects. On the other hand, mutant Lyp R620W is cat- and protection against viral infection [133]. Ample evidence also links alytically more active [113] which would mean that it could potently human PTPRC to immunodeficiency disorders and virus susceptibility. suppress TCR signaling during thymic development, enabling the surviv- A severe combined immunodeficiency (SCID) patient displayed loss of al of autoreactive T cells that would normally be eliminated by negative functional CD45 due to compound heterozygosity; one allele suffered selection. Recently, however, it was demonstrated that the R620W Lyp from a large deletion while in the other allele the intron 13 donor splice isoform is degraded more rapidly as comparedtothewildtypeprotein site was destroyed by a G-to-A transition [134]. Another SCID patient as a result of an increased interaction with and subsequent cleavage by was found to carry a small deletion in exon 11 of PTPRC,resultingina calpain 1, a calcium-dependent protease [114]. Thus, reduced Lyp levels 2-amino-acid-deletion in the extracellular fibronectin type III (FNIII) may neutralize any gain in specific activity of the R620W isoform. It will domain that prevented expression of the mutant molecule on the cell be insightful to hear about the protein stability of the Lyp R263Q variant surface [135]. Also uniparental disomy for an inactivating mutation in as well in due course. CD45 has been added to the list of SCID molecular etiologies [136]. Intriguingly, the R620W allele is absent in African and Asian popula- A causative role in multiple sclerosis (MS) has been proposed tions which may reflect a trade-off between protection from infections based on knockout mouse experiments [137] and the finding that a and susceptibility to autoimmune diseases. The R620W polymorphism SNP within PTPRC was associated with MS in several families [138]. also correlated with the risk of primary resistance to imatinib therapy The SNP results in a C-to-G transversion in PTPRC which does not in chronic myeloid leukemia patients, suggesting a role for Lyp in lead to an amino acid change but rather blocks the alternative splicing BCR-ABL-related signaling pathways [115]. Potential physiologic sub- out of exon 4 [139]. However, results of subsequent, much larger strates of Lyp include TCR zeta, CD3 epsilon, Lck, and ZAP70, among studies rather argue against an association between this PTPRC others [116]. In a recent study [117], the cytosolic adaptor protein 77C-G SNP and MS ([140] and references therein). Interestingly, dur- SKAP-HOM has also been identified as a Lyp substrate, and corresponding the course of these studies it was noted that the 77C-G allele was ing X-ray structural data now provide a start to develop therapeutics found at a much higher frequency among hepatitis C virus-infected that target Lyp and thus may alleviate multiple autoimmune diseases. patients than in healthy controls [141]. Also, 77C-G heterozygotes It will be crucial, however, to learn what the net result of Lyp- are much more frequent among chronic hepatitis C virus carriers R620W's decreased protein stability in combination with its increased than individuals who resolved hepatitis C virus infection and it is of enzymatic activity actually is. Importantly, the number of regulatory T note that 77C-G homozygotes were not detected in any of the groups. cells in the mouse thymus were found to correlate inversely with Lyp Subsequent studies on patient-derived lymphocyte populations and 1682 W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 generation of transgenic mice provided a glance of the underlying the molecular mechanism underlying PTPRD's tumor suppressive link mechanism leading to the increased susceptibility to hepatitis C virus in clear cell renal cell carcinoma may also come down to an aurora infection among 77C-G heterozygotes [141]. The 77C-G SNP enhances kinase-dependent upregulation of the Myc oncoprotein. A further de- inclusion of the exon 4-encoded “A” part in CD45 splice isoforms. This scription of PTPRD somatic mutations in cancer can be found elsewhere causes an increase in CD45RA+ primed CD8 T cells, in which dephos- [6,7]. phorylation and activation of Lck is enhanced. Transgenic mice that mimic this increased CD45RA+ expression also display an altered 3.4. PTPRF CD8+ T cell phenotype, including enhanced proliferative responses and Lck activation as observed in human peripheral blood mononuclear PTP LAR, a very close homolog of RPTPδ, is encoded by gene PTPRF;it cells. Thus, the 77C-G PTPRC allele results in a more vigorous—and per- also represents an RPTP with extracellularly a collection of Ig-like and haps non-protective—response and increased disease severity upon FNIII repeats reminiscent of neural cell adhesion molecules. Ptprf mu- hepatitis C virus infection as compared to the normal allele. tant mice show several abnormalities that underscored a role for LAR PTPRC is now also added to the expanding list of RA risk genes [142]. in mammary gland development and neuronal development and func- The involved SNP (rs10919563) resides within an intron, some 35 kbp tion [155–159]. Although PTPRF mutations have been encountered in away from the previously discussed C77G SNP that altered PTPRC splic- somatic pathologies, until recently germline mutations were not ing. Intriguingly, many RA risk SNPs appear located near genes involved reported. This has now changed with the incidental reporting on a in TNFα signaling and thus may affect expression regulation of the near- syndromic amastia patient that presented an inherited reciprocal bal- by genes. Furthermore, RA risk alleles proved worthy in categorizing RA anced translocation involving PTPRF [160]. Amastia is the complete ab- patients in clinically meaningful groups, including responsiveness to sence of breasts, resulting from complete failure of mammary ridge anti-TNF therapy. Indeed the PTPRC RA-associated SNP was found re- development in utero, an extremely rare disorder that displays both au- peatedly to predict responsiveness to anti-TNF therapy [143,144] and tosomal dominant and autosomal recessive modes of inheritance. In future work thus should reveal whether it is CD45 or rather a nearby lymphoblastoid cells derived from the affected individual, sharply con- TNFα pathway component that could explain the disease link. trasting with findings in materials from her unaffected relatives that also carried the interrupted PTPRF allele on the maternal chromosome, 3.3. PTPRD severely reduced PTPRF mRNA levels and absence of LAR protein was found. This implies that the proband's paternal PTPRF allele harbors Restless legs syndrome (RLS) is an autosomal dominant disorder some pathogenic mutation as well but sequence analysis of the tran- that is characterized by nocturnal periods with an irresistible desire to scription unit and promoter region did not yield the desired evidence move the legs that on the long run cause insomnia and chronic sleep but confirmed that the non-affected carrier sisters inherited the other deprivation. Currently, dopaminergic agonists are used for treatment allele of the deceased father [160]. Further examples of such germline but, oddly enough, genes involved in dopaminergic transmission are PTPRF mutations should corroborate these findings and may provide not associated with the disorder. Instead, the predisposing loci that the materials to delineate the consequences of reduced LAR levels at thus far have been identified rather relate to limb development, iron the molecular level that may explain this developmental abnormality. storage and spinal cord interneuron development [145].Thesuscepti- LAR has been put forward as an important negative modulator of the bility locus on chromosome 9p24–p22 has been subject of debate for insulin signaling pathway [161–163]. However, RNAi-mediated knock- some time [146] but two independent studies now have settled the down of LAR in HEK293 cells did not affect IR and IRS phosphorylation issue by demonstrating an association of RLS with the gene PTPRD at levels but rather altered downstream Akt/PKB and MAP kinase activities 9p24–p23 [147,148]. These studies concentrated on two independent [164]. Although endogenously LAR is hardly expressed in muscle [165], SNPs that reside in PTPRD introns but that end up in the long 5′ its overexpression in muscle tissue of transgenic mice also resulted ex- untranslated region of brain-specific alternative transcripts. PTPRD en- clusively in post-receptor effects; IR and IRS-1 phosphorylation appeared codes RPTPδ, an RPTP with FNIII and immunoglobulin (Ig) type cell ad- normal whereas IRS-2 phospho-levels and associated PI3-kinase activity hesion motifs in its extracellular part. How these PTPRD variants confer were reduced, causing whole-body insulin resistance [166].Agenetic risk of RLS remains as yet enigmatic but, based on findings in Ptprd variant of the human PTPRF promoter pointed to an association with fea- knockout mice [149], it is tempting to postulate that altered stability tures of insulin resistance in two different cohorts, although an effect by of PTPRD transcripts will have bearing on motor neuron axon guidance the variant on promoter activity could not be detected [167]. Since insu- and termination during limb development and function. Furthermore, lin resistance is pathogenic for coronary artery disease, particularly since the RPTPδ extracellular segment is able to interact with Ig-like do- amongst patients with type 2 diabetes, an association with PTPRF gene mains of interleukin-1-receptor accessory protein-like proteins [150], variants was tested for this patient group. Both an Italian study [168] which are implicated in cognitive impairment disorders and can induce and data from the Wellcome Trust Case Control Consortium [41] reveal dendritic spine formation, PTPδ mutations may also contribute to RLS that the minor allele at rs2782641 associates with coronary artery dis- by impacting on trans-synaptic signaling events. ease in patients with type 2 diabetes, likely in a recessive model of inher- Another PTPRD SNP, rs2279776, representing a silent mutation in itance. The SNP locates in PTPRF intron 3, suggesting that a mechanistic the codon for amino acid residue 1418 that resides within the first explanation should be sought at the transcriptional or alternative splic- PTP domain, has now been associated with a higher risk to develop ing level. clear cell renal cell carcinoma [151]. Together with two intronic PTPRD SNPs, rs2279776 has also been instrumental in associating PTPRD with 3.5. PTPRJ pediatric asthma occurrence in Taiwan [152]. The cancer risk allele resulted in significantly lower RPTPδ immuno-reactivity in renal tissue Density-enhanced phosphatase-1 (DEP-1) is a widely expressed [153], further implicating RPTPδ as a tumor suppressor protein. Earlier RPTP that is encoded by the PTPRJ gene. Studies in mice provided evi- reports had already pointed to PTPRD loss-of-function mutations in dence that the gene is important for vascular development and that it neuroblastoma, the major childhood cancer arising from precursor represents a colon cancer susceptibility locus [169–171]. Although on cells of the sympathetic nervous system [154]. In those studies it the basis of sporadic human tumor samples a potential tumor suppres- appeared that RPTPδ interacts with and dephosphorylates aurora kinase sor activity for DEP-1 could be suggested, no spontaneous tumor devel- A (AURKA), an oncogenic protein that is over-expressed in multiple opment was observed in DEP-1 deficient mice [172]. A recent study cancer types. This dephosphorylation results in aurora kinase A degra- revealed that PTPRJ also represents a colorectal cancer susceptibility dation and thus eliminates its role in Myc stabilization [154]. Likewise, locus in human. In two patients with early-onset microsatellite-stable W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 1683 colorectal cancer without polyposis and with an apparently recessive patients are reminiscent of the phenotype in Ptpro mutant mice. Using mode of inheritance, a large intragenic duplication was identified that an unbiased approach, via SNP-based genome-wide analysis and homo- affected the PTPRJ 5′ end [173]. This micro-duplication resulted in epi- zygosity mapping, a homozygous c.2627+1G>T donor splice-site mu- genetic silencing of the variant PTPRJ allele, in concurrence with copy tation was identified in a single family, that results in the splicing out number variation-based epimutation mechanisms in a subgroup of of exon 16 in GLEPP1 mRNA. Investigation of additional families re- Lynch syndrome patients with hereditary non-polyposis colorectal can- vealed a second, distinct homozygous c.2745+1G>A donor splice-site cer [174]. Additional mutations in the other PTPRJ allele were not ob- mutation in PTPRO, this time causing skipping of exon 19 and degrada- served in one of the patient's tumor material [173], suggestive of an tion of the aberrant mRNA via nonsense-mediated decay. Thus, PTPRO obligate haploinsufficiency scenario as recently put forward for mutations underly autosomal-recessive nephrotic syndrome type 6. In tumor-related PTEN (phosphatase and tensin homolog) mutations view of the nature of other glomerular disease genes (including those [175]. In addition, it has also been found that specific PTPRJ haplotypes encoding nephrin, podocin, phospholipase CE1, α-actinin-4, TRPC6, confer different protective effects on breast cancer, papillary thyroid formin, Wilms' tumor suppressor protein and laminin B2 [192])and carcinoma, head and neck squamous cell carcinoma and lung carcinoma the nature of its substrates [193,194] it remains open whether GLEPP1's risks [94,176,177]. The molecular basis of the phenomenon has not yet contribution to glomerular function depends on its capacities as a cell been explored but it may touch upon DEP-1's ability to interact with adhesion molecule, its impact on the submembranous cytoskeleton and dephosphorylate cell junction proteins [178].Finally,SNPsin via intracellular signaling events, or both. PTPRJ that result in amino acid changes that probably affect DEP-1 li- A recent genome-wide study found an association of three PTPRO gand binding capacity, oligomerization and/or phosphatase activity, intronic SNPs with learning and memory functions in neurocognitive were found enriched in patients with heparin-induced thrombocytope- disease patients with schizophrenia spectrum disorder or bipolar nia, suggesting a regulatory role for PTPRJ in this thrombosis-related disorder [195].Earlierfindings in Ptpro mutant animals had pointed disease [179]. This would be in line with observations in Ptprj knockout to subtle abnormalities in nerve development [196].Thismouse mice that, next to the SFK-mediated regulatory function of DEP-1 in study entailed tests addressing sensorimotor coordination and sug- B-cells and macrophages [180], also display a bleeding tendency and de- gested both nociception and proprioception to be perturbed. Also fective arterial thrombosis [181].Furthermore,thisputsforwardthatsuch using the in vitro PC12 cell model a major role for GLEPP1 in nerve PTPRJ polymorphisms also may impact on airway hyperresponsiveness growth factor-induced neuronal process outgrowth, through de- [182] and bacterial infections [183]. phosphorylation of interacting protein NPCD, has been demonstrated [197]. Taken together, this urges for substantiation of the human 3.6. PTPRN2 genetic findings and for tests on the cognitive abilities of GLEPP1 deficient mice. Two PTP genes, PTPRN and PTPRN2, encode major autoantigens in type 1 diabetes mellitus that function in secretory vesicle release as revealed by mouse studies [184]. For a long time it was thought that these 3.8. PTPRQ transmembrane PTPs had no catalytic activity themselves and might perhaps protect phosphotyrosine-containing proteins from being An interesting case is provided by the PTPRQ gene, which also en- dephosphorylated by other PTPs through specific association involving codes an RPTP with multiple extracellular FNIII repeats and a single intra- their impotent catalytic site [185]. However, quite recently evidence cellular catalytic PTP domain. PTPRQ favors inositol lipid phosphates was obtained that phogrin, the protein encoded by gene PTPRN2,actu- over tyrosine-phosphorylated proteins as substrates [198]. Mutations ally does display phosphatase activity but rather towards inositol phos- in PTPRQ cause autosomal recessive nonsyndromic hearing loss-84 pholipids than tyrosine-phosphorylated proteins [186]. The study (DFNB84), as was found in two unrelated families with sensorineural suggests that phogrin activity towards PI(4,5)P2 is instrumental in se- hearing loss and vestibular dysfunction [199,200]. Several years earlier, cretory vesicle release, and this may well bear relevance for synaptic studies in mice already predicted this outcome [201].MousePtprq is neurotransmitter-dependent processes that are disturbed in neuropa- expressed in inner-ear, cochlea and vestibule hair bundles and animals thologies. Investigating copy number variations in a large cohort of at- carrying mutations in gene Ptprq had no shaft connectors in vestibular tention deficit hyperactivity disorder patients led to the assignment of hair bundles and misaligned or absent stereocilia. The mutant mice PTPRN2 as one of many candidate susceptibility genes [187].Aseparate showed rapid postnatal deterioration in cochlear hair-bundle structure, genome-wide linkage scan, to identify genetic factors determining progressive loss of affected hair cells and ultimately deafness [201]. co-occurrence of cocaine dependence and major depressive episode Thus the PTPRQ protein is required for the formation of the shaft connec- with poor treatment outcome and high relapse risk, yielded four prom- tors, normal maturation and long-term survival of cochlear hair cells. Re- ising candidates including PTPRN2 [188]. Replication of these findings is cent work on the mouse model also corroborated PTPRQ involvement in however mandatory before we might start speculating on possible vestibular dysfunction [202]. translational spin-offs. Human PTPRQ encodes several splice variants that differ in the number of FNIII repeats in the long extracellular segment of the transmem- 3.7. PTPRO brane PTP. The nonsense mutation that was found in exon 19 of PTPRQ in DFNB84 patients predicts a truncated protein with a reduced number PTPRO encodes glomerular epithelial protein 1 (GLEPP1), an RPTP of FNIII repeats (one to five, depending on the splice isoform). Also the with multiple extracellular FNIII repeats and a single intracellular cata- Arg-Gly missense mutation that was encountered in exon 19 would af- lytic PTP domain. Highest GLEPP1 expression levels are seen in the glo- fect an FNIII domain; the substitution of a big positively charged residue merulus of the human kidney [189]. GLEPP1 deficiency in mice leads to by a small uncharged one may well be incompatible with essential in- aberrant podocyte structures and reduced glomerular filtrative capaci- teractions mediated by the wild-type protein or, alternatively, the mu- ty, indicating that Ptpro plays an important role in pressure/filtration tant protein may not reach the cell surface. Intriguingly, although PTPRQ rate physiology in mice [190]. It should therefore not come as a surprise is also expressed in other tissues where stereocilia play important roles, that in a recent study a distinct set of idiopathic nephrotic syndrome pa- no symptoms other than deafness and vestibular dysfunction were tients were found to suffer from a homozygous mutation in PTPRO reported [199,200]. Equally intriguing remains the question whether [191]. Idiopathic nephrotic syndrome is characterized by proteinuria, PTPRQ functioning solely relies on its extracellular adhesive talents or hypoalbuminemia and edema, resulting in end-stage kidney disease if whether the catalytic activity towards its phospholipid substrates is rel- untreated. Reported defects in podocyte structure and function in evant as well. 1684 W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696

3.9. PTPRR tandem intracellular phosphatase domains, and have extracellular car- bonic anhydrase and FNIII repeats. The difference lies in the length of This gene encodes several receptor-type, internal vesicle-associated, the spacer region between the transmembrane and FNIII repeats; and cytosolic isoforms, whose expression in cerebellar granular layer RPTPZ-A is highly modified with chondroitin sulfate in the spacer region, and Purkinje cells is regulated during development [203]. Ptprr knock- whereas RPTPZ-B has a shorter, less-modified spacer domain. RPTPZ is a out mice display mild, ataxia-like, locomotive impairment [204]. receptor for the cytokine pleitrophin. Soluble RPTPZ (also known as PTPRR proteins are major regulators of subcellular distribution and cat- phosphacan) corresponds to the extracellular portion of RPTPZ-A includ- alytic activity of the MAP kinases ERK1/2, ERK5, and p38α,bymeansof ing the modified CS domain, and is highly N-and O-glycosylated [222]. direct physical interaction and dephosphorylation [205–208].An Ptprz knockout mice have been generated and mild changes in myelin ul- intronic SNP at PTPRR has been associated with major depressive disor- trastructure, spatial learning defects and altered B cell levels were en- der (MDD) in a Chinese female population. Although the functional out- countered [223–225]. However, subjecting these mice to experimental come of this PTPRR polymorphism is unknown, the correlation between autoimmune encephalomyelitis, a well-established mouse model of low neuronal ERK1/2 activation and mood disorders in humans and in MS, revealed a defect in remyelinating capacity in vitro and the process mouse models [209,210] points to increased PTPRR activity in this dis- of remyelination in vivo, which manifested as sustained paralysis associ- ease. This is in line with the gain-of-function properties attributed to ated with a loss of mature oligodendrocytes in the spinal cord [226]. the PTPRR-related protein, STEP, in the etiology of schizophrenia PTPRZ1 expression is elevated in remyelinating oligodendrocytes at MS ([56]; see above). Moreover, the expression of another MAP kinase lesions, suggestive of a link between PTPRZ1 and demyelinating disease. inactivator, DUSP1/MKP1 (discussed further on), is increased in the hip- However, current MS susceptibility loci reside on chromosomes 1p36, pocampus of MDD patients, and increased hippocampal DUSP/MKP1 5p13, 6q21, and 10p15 and do not include PTPRZ1 on 7q31.3. Further- expression in rat and mouse models causes depressive-like behaviors more, a recent study on an independently and differently generated [211]. Ptprz knockout mouse strain did not recapitulate the previous experimental autoimmune encephalomyelitis findings and rather pointed to 3.10. PTPRS a negative regulatory role for RPTPZ isoforms in oligodendrocyte differentiation and remyelination [227].InyetathirdPtprz knockout mouse The cell adhesion molecule (CAM)-like RPTPs LAR and RPTPδ that model, and using a distinct experimental demyelination protocol, also are implicated in amastia and restless legs syndrome, respectively, no impairment of in vivo remyelination was detected and instead an im- have already been discussed. In humans there is one more gene that en- portant role in the maintenance of axonal integrity under demyelinating codes such a transmembrane PTP with Ig-like and FNIII type repeats in conditions was disclosed [228]. Either way, RPTPZ proteins remain im- the extracellular part; the gene is termed PTPRS and the encoded pro- portant targets of axonal protection in inflammatory demyelinating tein is RPTPσ. Ptprs mutant mice display a phenotype that betrays im- diseases. portant roles in nervous system and pituitary gland development Triggered by the observation in a cell model that PTPRZ1 expression [212]. The mice were also found to spontaneously develop mild colitis levels match the degree of cell vacuolation induced by the Helicobacter that could be readily worsened by providing an experimental challenge pylori virulence determinant protein VacA, Noda and coworkers exam- [213]. This led to an investigation whether SNPs in human PTPRS are as- ined pathogenicity of H. pylori, a primary pathogen in benign and malig- sociated with ulcerative colitis. Indeed three intronic SNPs significantly nant gastroduodenal disease, in Ptprz knockout mice [229].This associated with ulcerative colitis and investigation of RPTPσ transcripts revealed that VacA binds to the PTP and thereby affects phosphorylation in lymphoblast cell lines that carry the successive SNPs demonstrated signaling in gastric epithelial cells, which leads to cellular detachment that the risk alleles favor exon 9 skipping, which results in deletion of explaining gastric injury and ulceration. Whether this has bearing for the third immunoglobulin-like domain in the extracellular part of the human population remains to be investigated. RPTPσ [213]. This may well have bearing for ligand recognition and sub- A cohort study covering 1400 patients diagnosed with schizophrenia strate dephosphorylation and consequently alter barrier defense in showed association between specific PTPRZ1 SNPs and schizophrenia in colon tissue. It is noteworthy to mention that adherens junction pro- the British population [230,231]. The schizophrenic patients displayed teins E-cadherin and β-catenin [213] and the actin cytoskeleton regula- a higher expression of RPTPZ-B isoform [232].However,otherwork tor p250GAP [214] are among the RPTPσ substrates. The latter may well has failed to demonstrate a similar linkage in the Japanese population explain the inhibitory effect of RPTPσ on nerve outgrowth and regener- [233]. Recently, it was reported that transgenic mice overexpressing ation [215,216]. the human PTPRZ1 locus developed schizophrenic-like changes in behav- Additional RPTPσ substrates are the RTKs Ret and EGFR [217–219]. ioral tests [232] and that RPTPZ expression is altered in amygdalas of The insulin receptor may appear an attractive substrate as well but in- schizophrenic patients [234]. Collectively, these studies suggest that vestigation of the insulin hypersensitivity featured in RPTPσ deficient RPTPZ could be involved in schizophrenia. Furthermore, the data are in- mice [220] rather led to the exclusion of RPTPσ as a direct modulator dicative of a role for RPTPZ in the modulation of neuregulin/ERBB4 and of insulin receptor signaling in peripheral insulin responsive tissues. Fyn signaling as the molecular basis of schizophrenia [230].Many Given RPTPσ's neuroendocrine impact on the regulation of glucose RPTPZ substrates [235,236] also provide ample ground for speculations homeostasis [220] it may still have bearing for diabetes etiology. Poly- on a possible underlying mechanism. morphisms in the gene were therefore scrutinized for an influence on the development of impaired glucose tolerance and type 2 diabetes in 4. Cys-based DUSP PTPs a Swedish cohort [221]. Indeed three SNPs (two in intronic parts of PTPRS and a synonymous one within exon 33) were found associated 4.1. DUSP1 with an increased risk of developing type 2 diabetes. Replication of these findings and concomitant allele-specific PTPRS expression stud- The DUSP1 gene encodes the MAP kinase phosphatase 1 (MKP1), the ies are now required to clarify this further. founding member of the MAP kinase phosphatase family of dual- specificity phosphatases (DUSPs) [237,238]. MKP1 is a nuclear, induc- 3.11. PTPRZ1 ible, and ubiquitous enzyme that dephosphorylates and inactivates the MAP kinases JNKs, p38s, and, to a lesser extent, ERK1/2. MKP1 PTPRZ1 encodes 4 isoforms, resulting in two transmembrane prod- plays an important role as an immune system modulator and as a medi- ucts, RPTPZ-A and -B, and two soluble, secreted products in the develop- ator of the anti-inflammatory effects of glucocorticoids, as well as a reg- ing and adult nervous system. RPTPZ-A and -B harbor the classical dual ulator of cell survival in cancer-related processes [8,239]. Multiple W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 1685 phenotypes have been associated with Dusp1 knockout mice, including PTEN gene an important diagnostic tool for patients [265]. In addition, increased innate immune responses and inflammatory cytokine produc- patients with PHTS also manifest increased risk of obesity, and de- tion, and sensitivity to induced arthritis [239,240]. In line with this, a creased risk of type 2 diabetes due to enhanced insulin sensitivity DUSP1 SNP (rs881152) targeting the gene promoter region was associat- [266]. It is likely that patient-specific PTEN mutations render different ed with bronchodilator responsiveness of multiethnic asthma patients PTEN functional properties and distinct clinical manifestations of can- treated with inhaled corticosteroids [241]. The preventive role of MKP1 cer, developmental, and metabolic diseases. For instance, a more in asthma is further sustained by the finding that MKP1 expression is deleterious PI(3,4,5)P3-phosphatase functional pattern has been ob- up-regulated by corticosteroids in airway smooth muscle cells, which served in PTEN mutations found in PHTS than in mutations found in mediates the inhibition of TNF-α-induced pro-inflammatory IL-6 and autism spectrum disorders/developmental delay patients [267]. IL-8 secretion [242,243]. Mechanistically, MKP1 up-regulation in airway Homozygous deletion of Pten in mice is embryonic-lethal [268],and smooth muscle cells seems to be mainly due to increased mRNA stability most of tissue-specific Pten knockout mice display enhanced tumori- and protein stabilization, suggesting a potential MKP1-mediated thera- genesis in the targeted tissues [269]. Remarkably, in a conditional peutic role in asthma for proteasome inhibitors or for inhibitors of mouse model of Pten loss in the prostate, acute Pten inactivation triggers MKP1 mRNA degradation [243,244]. Thus, analysis of MKP1 protein an anti-proliferative, p53-dependent pro-senescence response, which levels in response to asthma therapies, as well as DUSP1 polymorphism has been proposed as a candidate pathway for prostate cancer therapy linkage to other human inflammatory diseases, is warranted. [270]. Tissue-specific Pten knockout in thyrocytes displayed goitre and thyroid adenomas, which is symptomatic of Cowden syndrome [271]. 4.2. DUSP6 On the other hand, tissue-specific knockout of Pten in neurons does not result in neoplasia, but rather in enlargement of brain structures Gene DUSP6 encodes MKP3, a cytoplasmic dual-specificity phospha- and abnormal synapse growth and plasticity, accompanied in some tase that dephosphorylates and inactivates ERK1/2 [245].MKP3isin- models by behavioral abnormalities. These phenotypes are reminiscent volved in down-regulation of ERK1/2-mediated signaling during of one of the PHTS manifestations associated with macrocephaly vertebrate development, and Dusp6 knockout mouse models display (Lhermitte–Duclos disease), or of autism spectrum disorders and devel- dwarfism-related skeletal abnormalities and cardiac hypercellularity opmental delay [272–274]. Heterozygous Pten knockout mice recapitu- [246,247].HumanDUSP6 maps to chromosome region 12q22–q23, late at the molecular and pathological level some of the symptoms one of the reported bipolar disorder loci, and SNPs within the coding observed in PHTS and autism spectrum disorders/developmental part of DUSP6 (p.Leu114Val and p.Ser144Ala) may contribute to bipolar delay patients [275], and are therefore suitable tools for the validation disorder in the Korean, but not the Japanese, female population and improvement of therapies. [248,249]. Functional analysis suggested a dominant enhancing effect Germline PTEN mutations found in patients not only affect PTEN cat- of these mutations on MKP3 phosphatase activity, which would be in alytic activity, but also PTEN protein stability and steady-state levels concordance with the hypoactivity of the ERK1/2 pathway detected in [276]. Studies in mice with hypomorphic Pten alleles have proved that some bipolar disorder patients [250]. Interestingly, residue Leu114 a small reduction in PTEN levels favors cancer onset [277],whereas forms part of a Leu-rich sequence in the MKP3 N-terminal regulatory transgenic mice with systemic overexpression of PTEN are resistant to domain, which is substituted by valine in the two MKP3-related cancer and obesity [278,279]. In line with this, different polymorphic MKPs, DUSP7/MKPX and DUSP9/MKP4. Further genetic and functional variants of PTEN gene have been negatively or positively correlated analysis of these MKP3 polymorphic variants is necessary to understand with risk to distinct human cancers, likely by affecting PTEN transcrip- the putative involvement of MKP3 in bipolar disorder. tion [280–284].Finally,differentPTEN SNPs have been associated in Chi- In two reports a SNP near the DUSP9 gene (rs5945326) was found as- nese populations with risk to atherosclerotic cerebral infarction and sociated with type 2 diabetes susceptibility [251,252]. As yet it is unclear coal smoke-linked chronic obstructive pulmonary disease [285,286].It whether DUSP9 expression is affected by the SNP. Therefore we refrain is likely that small variations in PTEN expression or function are rele- from a further discussion and only listed this PTP gene in Fig. 1. vant for the susceptibility of a wide array of human pathologies. Multi- ple avenues are open to restore or interfere with PTEN biological 4.3. Phosphatase and tensin homolog PTEN activity in the treatment of human disease.

PTEN is undoubtedly as yet the most relevant PTP family member 4.4. PTP4A1 from a human disease viewpoint. This unique lipid phosphatase counter- acts the oncogenic phosphatidylinositol 3-kinase by dephosphorylating PTP4A1 gene encodes PRL-1, the founding member of the phospha- the D3 position of phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P3]. tase of regenerating liver phosphatases (PRLs; PRL-1, -2, and -3). PRLs By virtue of this activity, PTEN is a major tumor suppressor protein are small DUSPs with oncogenic and metastatic activities, which mostly whose function is essential to control cell growth and development and rely on their catalytic activity, although their physiological substrates to prevent tumorigenesis. Accordingly, loss-of-function mutations in the remain uncertain. PRLs are C-terminally prenylated proteins that shut- PTEN gene are found with high incidence in sporadic human cancers tle between the nucleus, the plasma membrane, and internal mem- [253,254]. PTEN protein is ubiquitously expressed and shuttles between branes. In general, PRLs are widely distributed and induced upon cell membrane, cytoplasm and nucleus. The biological activity of mitogenic stimulation, and are over-expressed in malignant human membrane-associated PTEN is the direct dephosphorylation of PI(3,4,5) cancers [287–289]. PRL-1 promoting-activity on cell migration and in- P3, although protein phosphatase activity, as well as nuclear functions, vasion has been related with a positive regulation of the Src/p130Cas, arealsoascribedtoPTEN[255–260]. RhoA/Rock, and ERK1/2 pathways [290,291]. Also, a role for PRL-1 in Heterozygous germline mutations in the PTEN gene are associated promoting cell cycle progression, likely by up-regulation of CDK2 and with hamartomas and hereditary tumor susceptibility syndromes Cyclin A, and down-regulation of p21 levels, has been proposed [292]. (including Lhermitte–Duclos disease and Cowden, Bannayan–Riley– A genome-wide association analysis found a significant correla- Ruvalcava and proteus syndromes) that have been clustered as tion of several SNPs at gene PTP4A1 with risk for alcohol dependence, PTEN hamartoma tumor syndromes (PHTS), as well as with autism most of which were found to be functional by mRNA expression data spectrum disorders and developmental delay. Mutations are found from HapMap database [293]. This is concordant with genome-wide all over the PTEN gene, including the promoter and splicing intronic expression analysis showing significant increase in PTP4A1 mRNA ex- regions [261–264]. The clinical manifestations of these syndromes pression upon ethanol consumption in mice [294]. Further molecular are highly variable, making the molecular analysis of the status of analysis is required to validate PTP4A1 as a genetic trait of alcohol 1686 W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 dependence in humans, and to make inferences on the putative func- Mtmr14 knockdown zebrafish embryos also showed increased tion of PRL-1 on this dependence and its relation with PRLs oncogenic autopaghy and myofiber hypotrophy, as well as impaired muscle ex- activity. citation–contraction and compromised motor function. Remarkably, an additive effect in the impairment of motor function was observed 4.5. Myotubularin-related proteins in zebrafish upon knockdown of both Mtm1 and Mtmr14 expression [318], suggesting compensatory effects in the functions mediat- Mytotubularin and myotubularin-related proteins (MTMR) consti- ed by these enzymes. tute a group of active and inactive DUSPs that contain one PTP domain and several protein- or lipid-interaction regulatory domains. Active 4.8. MTMR2 and SBF2 MTMRs dephosphorylate the D3 phosphate from phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating Two other MTMRs, MTMR2 and MTMR13 (encoded by gene SBF2), phosphatidylinositol and phosphatidylinositol 5-phosphate, respec- are involved in the pathogenesis of the Charcot-Marie-Tooth (CMT) de- tively. Since these lipids play crucial roles in membrane functionality, myelinating neuropathies, which also manifest with muscle weakness including membrane remodeling, endosome and lysosome trafficking, and atrophy in the extremities [319,320]. In analogy with MTM1- and autophagy, MTMRs play an essential role in human physiology desmin interaction in skeletal muscle, MTMR2 associates physically in and disease [295–298]. In addition, myotubularins have been involved neurons with the neurofilament light chain protein (NF-L) that is mu- in the control of cell survival signaling through Akt/PKB and caspase tated in axonal and intermediate CMT neuropathies [321]. MTMR2 is pathways [299,300]. Functional defects in MTM1 and MTMR14 are an active phosphatase, but MTMR13 is inactive as an enzyme and rather associated with centronuclear myopathies, whereas mutations in directly regulates the activity of MTMR2 by heterodimerization [322]. MTMR2 and MTMR13 are causative of demyelinating neuropathies. Mutations in MTMR2 or SBF2 genes are causative of CMT4B1 and Other myotubularin-related genes represent risk alleles for various dis- CMT4B2 disease, respectively, which are symptomatically indistin- eases, as will be described further on. guishable [323–325],andMtmr2 and Mtmr13 knockout mice display a similar CMT4B-like phenotype [326–329]. An intronic SNP at SBF2 4.6. MTM1 gene (rs10734652) associated with stature variation in Caucasian and Chinese populations [330]. The myotubularin gene MTM1 is mutated in X-linked recessive myotubular (centronuclear) myopathy (XLMTM) [301–304] a severe 4.9. MTMR3, MTMR7 and MTMR9 neonatal disorder characterized by muscle weakness and hypotonia, as a result of abnormalities in the maturation and/or regeneration of Several SNPs that associate with human diseases have been detected skeletal muscle fibers. Skeletal muscle fibers from XLMTM patients dis- in some other MTM-related genes. These include SNPs at MTMR3 play centrally located nuclei that resemble fetal myotubes, and the ma- (rs17728461 and rs36600, susceptibility to lung and gastric cancer; jority of affected males die early after birth [305]. Mtm1 knockout mice rs2412973, susceptibility to childhood-onset inflammatory bowel disease recapitulate the human disease well, and display amyotrophy of skele- [331–333]), MTMR7 (linked to variant Creutzfeld-Jakob neurodegenera- tal muscle fibers as a result of defects in skeletal muscle structural main- tive disease; intronic variant rs4921542 [334],andMTMR9 (susceptibility tenance, which leads to death 6–14 weeks after birth. Skeletal muscle to metabolic syndrome and obesity; rs2293855 [335,336]). Follow-up contraction in Mtm1 knockout mice is defective due to T-tubule disorga- studies, to replicate these findings and to unravel the involved molecular nization [306,307]. Some MTM1 mutations, such as the missense muta- etiology, are eagerly awaited. tion rendering the Arg69Cys substitution, are associated with a mild XLMTM phenotype in patients, likely as the consequence of reduced 4.10. EPM2A MTM1 function or protein levels. A mouse p.Arg69Cys knock-in model also showed a mild phenotype in mice, illustrating that mutation- Laforin is a ubiquitously expressed DUSP that localizes in the cyto- related phenotypic variability in XLMTM patients can be mimicked in plasm and in the nucleus, binds to glycogen, and forms a molecular com- mouse models [303,308]. A dog model of MTM1 functional deficiency plex with malin, an E3 ubiquitin ligase. It has been proposed that the also reproduces human XLMTM disease [309] and MTM1 knock-down complex laforin-malin regulates the ubiquitination and proteasome- in zebrafish also showed T-tubule disorganization, with defects in mus- mediated degradation of proteins involved in glycogen metabolism, cle excitation-contraction coupling [310]. MTM1 binds to desmin, a and in the protein-degradation response to endoplasmic reticulum stress muscle-specific protein mutated in familial cardiac and skeletal myopa- [337–339]. Loss-of-function mutations in the genes encoding laforin thies, and disruption of MTM1-desmin complex results in an abnormal (EPM2A)ormalin(NLHRC1) account for more than 90% of the cases of intermediate filament network in skeletal muscle, independently of Lafora disease (LD), an autosomal recessive neurodegenerative disorder MTM1 catalytic activity [311]. Whether other MTM-related proteins that presents with progressive myoclonus epilepsy and neurological dys- regulate intermediate filament architecture deserves further studies. functions, and ends with death about 10 years after onset [340–343].A In line with the possibility of MTM1 phosphatase-independent func- pathological characteristic of LD is the presence of Lafora bodies, insolu- tions, viral gene transfer of catalytically inactive MTM1 ameliorated ble, poorly branched, and heavily phosphorylated glucose polymers that XLMTM-like phenotype in Mtm1 knockout mice [312]. Thus, MTM1 in- accumulate primarily in neurons from the central nervous system. Po- volvement in human myopathies goes beyond its catalytic activity. tential substrates of laforin include phosphorylated glycogen, glycogen metabolism-related proteins (such as GSK3-β) and Tau protein, although 4.7. MTMR14 it is believed that the physiologic and pathologic role of laforin may go beyond its phosphatase enzymatic activity [344–346]. MTMR14 (Jumpy, MPI) is mutated in patients with sporadic Laforin is required for the proper formation of autophagosomes, centronuclear myopathy, a muscular disease with milder manifestations and it has been proposed as a positive regulator of autophagy than XLMTM. Pathogenic mutations compromise PTP activity and its ca- [347,348]. Although contradicting findings have been reported on pacity to negatively regulate autophagy [313–315]. Mtmr14 knockout glucose metabolism and insulin sensitivity from laforin knockout mice displayed muscle weakness and fatigue, likely as a consequence of mice [349,350], it seems that glycogen metabolism and degradation Ca2+ leakage from the sarcoplasmic reticulum. In addition, these mice of macromolecules and/or organelles seem to be under the control displayed a decline in muscle function that is reminiscent of aging of laforin activity. Laforin has also been proposed to suppress tumor sarcopenia, in correlation with defective Ca2+ homeostasis [316,317]. growth in immune-compromised mice, to negatively regulate cell W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 1687 cycle progression and to confer resistance of cancer cells to apoptosis with branchio-oto-renal syndrome but is much more severe due to addi- [351–353]. However, thus far no genetic alterations in the EMP2A tional features like sloping shoulders, developmental delay and short gene have been reported to be associated with cancer. Laforin knockout stature [373]. Large deletions involving the EYA1 gene region were ob- mice recapitulate several LD symptoms, including laforin disease-like served in oto-facio-cervical cases, underscoring that oto-facio-cervical neuronal and behavioral disorders, and the presence of Lafora bodies, and branchio-oto-renal syndrome are allelic and suggesting that other particularly abundant in heart and brain, which increased with age deleted genes centromeric to EYA1 are responsible for the additional clin- [345,354,355]. In the brain, these mice displayed hyperphosphorylated ical features. Knock-down of the Eya1 ortholog interactors Sipl1 and Tau protein and neurofibrillary tangles, as well as prominent changes in Rbck1 in zebrafish caused a branchio-oto-renal syndrome-like pheno- expression of genes involved in post-translational modification of pro- type, supporting the role of Eya1 in the involved regulatory networks teins and transcriptional regulation [344]. In addition, increased endo- [374]. An extensive study towards risk alleles for vesico-ureteral reflux, plasmic reticulum stress and impaired proteasomal function was a consequence of ureteric budding defects, yielded a trend for EYA1 found in the liver, but not in the brain, of laforin knockout mice [356]. SNPs but so far significance was not reached [375]. Given EYA1's potency LD shows a high allelic heterogeneity, and a large number of distinct tocontrolepithelialcellfate—involving PKC, Notch and Shh pathways—it mutations have been found in LD-affected families, that include mis- nevertheless presents an appealing candidate. sense, non-sense, insertion, and deletion mutations [357]. The functional consequences of these mutations are variable, including total or 5.2. EYA4 partial lack of expression of laforin, altered subcellular location, defects in laforin phosphatase activity, or decreased binding to glycogen, malin Mutations in the fourth EYA-encoding gene in human, EYA4,have or regulatory proteins [340]. This likely contributes to the phenotype been identified in patients that present autosomal dominant non- heterogeneity observed in LD patients, although variability in the age syndromic sensorineural deafness type 10, illustrating that EYA4 is at onset of the disease has also been documented in patients harboring not only important during early embryogenesis but is essential for the same mutation [358], suggesting the involvement of genetic modi- continued functioning of the organ of Corti throughout adult life as fiers [340]. Remarkably, alternative splicing of laforin gene generates well [376–378]. Eya4 knockout mice phenocopy the disease and in phosphatase inactive isoforms that may act as dominant negative addition put forward EYA4 as a candidate predisposition gene for interactors of the active isoforms [359,360], and these interactions can human otitis media susceptibility [379]. In some kindreds sensori- also be affected by LD mutations. In addition, laforin variants exist neural hearing loss is followed by dilated cardiomyopathy and (e.g. p.Ala46Pro) that do not co-segregate with the LD phenotype, cor- heart failure [380] due to a large deletion in EYA4 that results in a se- roborating involvement of other genes in LD [361]. verely truncated EYA4 protein [381]. The picture emerges that nonsyndromic deafness is caused by EYA4 proteins with a deleted 5. Asp-based PTPs HAD domain but an intact N-terminal part, whereas syndromic hearing loss with dilated cardiomyopathy results from truncations in- The Drosophila Eyes absent (Eya) gene constitutes the prototype for volving the N-terminal domain of the protein as well [381,382]. class IV PTPs, and encodes a nuclear protein that is essential for eye de- Two additional genetic findings are worthwhile mentioning. First, a velopment. Operating both as transcription factor and as enzyme it is genome-wide strategy to identify genetic loci determining successful required for organ and tissue development in a variety of organisms, in- response to anti-TNF treatment in RA showed the strongest effect for cluding mammals [362]. EYA is a constituent of a transcription factor an intronic SNP within gene EYA4 [383] and further testing will be re- complex involving, in vertebrates, the SIX homeodomain proteins and quired to clarify this proposed relationship. Finally, a case has been de- the DACH transcriptional regulator. The phosphatase activity of EYA is scribed in which EYA4 was part of a large (10 Mbp) deleted region that instrumental for switching between transcriptional repression and acti- caused a mild, middle interhemispheric variant of holoprosencephaly vation states of the complex, and mutations that impair EYA catalytic (HPE, a congenital malformation of the developing human forebrain activity suffice to obstruct eye development [362]. EYA proteins operate in which the cerebral hemispheres are not properly separated) [384]. as phospho-tyrosine- and phospho-threonine-directed phosphatases; Intriguingly, EYA4 was found to interact with the nuclear transcription the N-terminal half carries phospho-threonine activity and the C- factor SIX3, which is encoded by a known HPE disease gene, and to terminal haloacid dehalogenase (HAD) domain contains the PTP activi- serve as co-activator [384]. Thus, EYA4 haploinsufficiency may contrib- ty [363]. Of interest, the EYA phosphatases display pro-angiogenic prop- ute to HPE through compromising SIX3 transcriptional activity. erties and are overexpressed in several human cancers, and EYA tyrosine phosphatase activity promotes breast cancer cell invasion, 6. Perspective transformation and metastasis, although the EYA substrates related with these functions remain unknown [364–367]. EYA proteins have After two decades of molecular research on PTPs, the field has also been proposed to regulate DNA damage repair by targeting the achieved major goals in the understanding of the biological properties DNA damage-related histone H2AX [368,369]. Identification of EYA of this family of enzymes, including their evolutionary history, reaction physiological substrates remains an important issue, especially now mechanisms, versatility of regulation, substrate specificity properties, that both human developmental defects and cancer have been attribut- and structure-function relationships [5]. Moreover, experimental evi- ed to impaired or dysregulated EYA activity. dence has been obtained on the active involvement of PTPs as drivers of major human pathologies, including a panoply of hereditary diseases 5.1. EYA1 and syndromes (Fig. 4). As for other enzymes, PTPs represent potential targets for pharmacological inhibition, and especially PTP1B has been In human there are four EYA genes, and loss of phosphatase activity extensively studied in this respect in view of its negative role in insulin mutations in EYA1 are associated with branchio-oto-renal syndrome signaling and, more recently, its positive role in cell growth and trans- [370]. Branchio-oto-renal syndrome is an autosomal dominant disorder formation [385]. Direct enzymatic inhibition of PTPs whose expression characterized by hearing loss, structural ear defects, branchial fistulas positively correlates with hereditary diseases, such as PTPN1 or or cysts, and renal abnormalities [371]. A spectrum of over eighty differ- PTPN5, may represent an effective palliative therapy. This, however, ent EYA1 mutations have been reported but a clear-cut correlation be- would require a new generation of PTP inhibitors with high bioavail- tween the severity of the phenotype and the involved EYA1 mutation ability and specificity before a clinical validation of this direct PTP inhib- or domain could not be extracted [372]. EYA1 mutations are also associ- itory therapeutic approach in the treatment of hereditary diseases can ated with oto-facio-cervical syndrome, which shares clinical features take place. Alternatively, the activation of physiological PTP-specific 1688 W.J.A.J. Hendriks, R. Pulido / Biochimica et Biophysica Acta 1832 (2013) 1673–1696 counteractors represents a complementary indirect route towards the manuscript. This work was supported in part by European Research same effect, and research in this area needs to be reinforced. 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