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Protein Tyrosine Phosphatase Variants in Human Hereditary Disorders and Disease Susceptibilities

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Protein Tyrosine Phosphatase Variants in Human Hereditary Disorders and Disease Susceptibilities Biochimica et Biophysica Acta 1832 (2013) 1673–1696 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis 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 var- iants 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 pro- tein 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 de- fects 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 num- ber 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
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