MINIREVIEW Protein tyrosine phosphatases: regulatory mechanisms Jeroen den Hertog1, Arne O¨ stman2 and Frank-D. Bo¨ hmer3

1 Hubrecht Institute, Utrecht, the Netherlands 2 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden 3 Institute of Molecular Cell Biology, Friedrich-Schiller-Universita¨t Jena, Germany

Keywords Protein-tyrosine phosphatases are tightly controlled by various mecha- catalytic activity; differential expression; nisms, ranging from differential expression in specific cell types to restricted dimerization; ligand binding; oxidation; subcellular localization, limited proteolysis, post-translational modifications phosphorylation; (R)PTP; (receptor) protein- affecting intrinsic catalytic activity, ligand binding and dimerization. Here, tyrosine phosphate; regulation; subcellular localization we review the regulatory mechanisms found to control the classical pro- tein-tyrosine phosphatases. Correspondence J. den Hertog, Hubrecht Institute, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands Fax: +31 30 251 6464 Tel: +31 30 212 1800 E-mail: [email protected]

(Received 27 October 2007, revised 10 December 2007, accepted 10 December 2007) doi:10.1111/j.1742-4658.2008.06247.x

Protein phosphorylation on tyrosine residues is an receptor (R)PTPs. Characterization of the catalytic important cell-signaling mechanism, controlled by the activities of PTPs indicated that their enzymatic activ- combined actions of protein-tyrosine kinases (PTKs) ity is extremely high with a kcat value up to three and protein-tyrosine phosphatases (PTPs). PTKs are orders of magnitude higher than that of the PTKs, the tightly regulated by various mechanisms. Whereas enzymatic counterpart of the PTPs. All cells express PTPs were initially regarded as household enzymes multiple PTKs and PTPs, therefore, tyrosine phos- with constitutive activity, dephosphorylating all the phorylation can occur in cells only if PTPs are tightly substrates they encountered, evidence is now accumu- regulated. Different levels of regulation can be dis- lating that PTPs are tightly regulated. As described cerned from the organismal through the cellular to the elsewhere in this minireview series, the human genome molecular level as indicated in Fig. 1. Here, we discuss encodes around 100 enzymes that have the capacity to the different regulatory mechanisms that have evolved. dephosphorylate phosphotyrosine (pTyr) in proteins [1,2]. We focus on the regulatory mechanisms of classi- Expression cal PTPs, a cysteine-based subclass of the PTP super- family that exclusively dephosphorylates pTyr in Differential expression of PTPs is an obvious regulator proteins. Classical PTPs comprise cytoplasmic and of PTP function. Among the PTPs are ubiquitously transmembrane proteins that are tentatively called expressed family members such as SHP2 or PTP1B,

Abbreviations EGF, epidermal growth factor; ER, endoplasmic reticulum; PDGF, platelet-derived growth factor; PrxII, peroxiredoxin II; PTK, protein-tyrosine kinase; PTP, protein-tyrosine phosphatase; pTyr, phosphotyrosine; ROS, reactive oxygen species; TGF, transforming growth factor.

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specific PTP mRNAs. An example is analysis of the PTP1B promoter, which identified a region involved in Differential expression in organs the induction of PTP1B expression by p210 BCR-Abl activity. This region was designated PRS and interacts with Egr-1 and SP-family transcription factors [18]. Y box-binding protein-1 (YB-1) is another transcrip- tional inducer of PTP1B and acts by binding to an enhancer element between -152 and -132 of the PTP1B Differential expression in tissues promoter [19]. In a recent search for novel Smad targets in transforming growth factor (TGF)b-stimulated mam- mary epithelial cells, the PTPj-encoding gene PTPRK was identified [20]. Although details of transcriptional regulation are still unknown, upregulation of PTPj through the Smad pathway seems to mediate several of Differential expression in cells the TGFb responses in these cells, including inhibition of cell proliferation and enhanced cell motility. Alternate use of promoters within PTP genes is another mechanism that can lead to tissue-specific PTP mRNA expression, as in the case of SHP1 [21], or to Subcellular localization the expression of different PTP isoforms, as for RPTPe. In the latter case, alternate promoter use leads to the expression of either a transmembrane RPTPe molecule or a soluble, cytoplasmic version of PTPe with presumably important consequences for the access Regulation at the molecular level to substrates [22]. Similarly, three distinct promoters can direct the generation of several isoforms of PTPRR proteins in neuronal cells, of which some are cytoplasmic [23]. Fig. 1. Regulation of PTPs at different levels. (top to bottom) PTPs Regulation of mRNA stability may be another are differentially expressed in specific organs, tissues or cells. Within cells, PTPs are directed to specific subcellular locations. At important level of control in PTP expression. In their the molecular level, PTPs are regulated by post-translational modifi- analysis of PTP genes, Andersen et al. [2] observed cations. that PTP genes often encode long 3¢-UTRs, which may be important in this respect. Very few studies have and more selectively expressed members that are abun- addressed this issue. For example, increased stability dant in neuronal or hematopoietic compartments [3–5]. of TC-PTP, but not PTP1B, mRNA has been observed However, in a given cell type, such as endothelial cells, in mitogen-stimulated T lymphocytes [24]. many of the 38 classical PTP genes appear to be Although largely unexplored, PTP levels are likely expressed, at least as represented by low mRNA levels to also be controlled at the levels of translation and [6] (see http://expression.gnf.org/cgi-bin/index.cgi). protein stability. Several PTP proteins exhibit rather PTP mRNA expression is regulated by different mech- long half-lives, for example, SHP2 [25], whereas short anisms. Induction of the expression of several PTP half-lives have been shown for different isoforms of genes has, for example, been reported upon neuronal PTPRR [26]. A cell-density-dependent increase in the or hematopoietic differentiation [7–11] and a number expression level of RPTPl has been attributed to a of PTPs are upregulated in cells reaching high densi- reduced rate of degradation when this PTP becomes ties, including DEP-1 [12], PTP-LAR [8], RPTPl [13], engaged in homophilic interactions upon cell–cell con- RPTPk [14], and PTPb ⁄ VE-PTP [15]. A highly tacts [27]. dynamic expression pattern for PTPs has been seen during the onset and termination of smooth muscle Subcellular localization cell proliferation in restenosis [16]. In cancer cells, mRNA expression of some PTPs is downregulated by Like protein phosphorylation, dephosphorylation by promoter methylation [17]. PTPs is required in a cell-compartment-specific man- Relatively few studies have addressed the detailed ner. Protein–protein interaction domains and compart- mechanisms involved in the transcriptional regulation of ment-specific targeting domains in PTPs serve to

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Fig. 2. Subcellular localization of PTPs. Cytoplasmic PTPs are recruited to activated cell-surface receptors by SH2, proline-rich FERM (band 4.1, ezrin, radixin, moesin hom- ology) and PDZ (postsynaptic density pro- tein 95, discs large, Zonula occludens) domains. RPTPs are also engaged in these complexes. Nuclear localization signals (NLS) and ER targeting domains direct PTPs to these compartments. A Sec14-homology domain (Sec14h) mediates functional associ- ation with secretory versicles. Cytoplasmic PTPs are recruited into lipid rafts by differ- ent domains. The kinase-interacting motif (KIM) in PTPs mediates binding to MAPK. Proteolysis releases the catalytic domain of (R)PTPs into the cytoplasm and possibly also into the nucleus. achieve the required PTP localization [28,29] from the published crystal structure revealed binding of PTP1B cell surface to the nucleus (Fig. 2). in a phosphotyrosine-independent manner to the At the plasma membrane, RPTPs regulate tyrosine ‘backside’ of the insulin receptor, an interaction that phosphorylation as it occurs in response to cell may facilitate the rapid engagement of substrate stimulation of PTK-coupled receptors [30] or in the residues upon insulin–receptor activation [42]. Interest- context of cell–cell or cell–matrix adhesion [31,32]. ingly, PTP1B can also be recruited to substrates via Complex formation of RPTPs with substrates is adaptor molecules. Phospholipase Cc1 serves as a important in these cases and has been shown, for scaffold downstream of the activated growth hormone example, with several RTKs [33,34]. RPTP domains receptor and recruits PTP1B by an as yet unknown which mediate such interactions remain to be identi- mechanism into a ternary complex with JAK2, lead- fied. In addition, cytoplasmic PTPs are recruited to ing to JAK2 dephosphorylation [43]. It will be inter- the sites of cell-surface tyrosine phosphorylation. esting to see if phospholipase Cc1, which binds to Paradigms are SHP1 and SHP2, which are recruited many cell-surface receptors, mediates the interaction to tyrosine-phosphorylated cell-surface receptors and of PTP1B with other targets as well. Recruitment of adaptor proteins through their SH2 domains [3,4], non-transmembrane PTPs to cell–cell adhesion com- whose recognition specificities have recently been plexes and cell–matrix adhesion complexes occurs, for elucidated in great detail [35]. Interestingly, the C-ter- example, via FERM and PDZ domains as in PTP- minus of SHP1 seems to be involved in targeting this BAS and via proline-rich domains as in PTP-PEST PTP to the plasma membrane. It has previously been [28,29,31,32]. shown, that the SHP1 C-terminus harbors a high- Some PTPs reside in the endoplasmic reticulum affinity binding site for acidic phospholipids [36]. (ER). The best investigated in this respect is PTP1B Recent studies revealed that this site is important for whose C-terminus contains an ER-anchoring hydro- targeting SHP1 to lipid rafts in T lymphocytes, where phobic sequence [39]. Spatial distribution of PTP1B it regulates T-cell receptor signaling [37]. Similarly, activity over the cell has recently been shown using HePTP is targeted to lipid rafts. In this case, targeting sophisticated FRET analyses. Most cellular PTP1B depends on prior phosphorylation by a PKC isoform activity resides in a perinuclear compartment, whereas [38]. Another non-transmembrane PTP that regulates the more peripheral PTP1B population has lower the tyrosine phosphorylation of surface receptors is activity [44]. How PTP1B can access sites of tyrosine PTP1B [39]. Very efficient substrate recognition by phosphorylation at the cell surface is the topic of this PTP occurs by its catalytic domain [40,41]. How- intense investigation. In the case of activated epidermal ever, non-catalytic interactions with substrates may growth factor receptor (EGFR) and platelet-derived also be important for PTP1B recruitment. A recently growth factor receptor (PDGFR), interaction with

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PTP1B takes place in conjunction with endocytosis at types and in response to certain cell stimuli, based on the surface of ER membranes, which extend far into a nuclear localization signal in its C-terminus, the cell periphery [45]. PTP1B, which remains bound however, the functional role of nuclear SHP1 remains to the ER, can also access cell–matrix adhesions and to be clarified [62]. SHP2 has been shown to dephos- this process involves microtubule activity [46]. Is there phorylate STAT5, however, in this case dephosphory- a function of PTP1B (and possibly other PTPs) in the lation occurs in the cytosol [63] and is unlikely to ER itself? One function seems to be the regulation of function in signal termination. Tyrosine-phosphory- ER stress [47]. Furthermore, it was observed early on lated STAT3 has been identified as a possible sub- that PTP1B can effectively dephosphorylate precursor strate of RPTPq ⁄ RPTPT [64]. This may occur molecules of cell-surface receptors, such as the insulin proximal to the receptor or an as yet unidentified pro- receptor or the EGF receptor in the ER, during bio- teolytic fragment of RPTPq may have access to genesis [48,49]. Recently, dephosphorylation of ER- nuclear pSTAT3. bound immature forms of different RTKs of the PDGFR family, notably of FLT3, has been shown to Alternative splicing and limited enhance their maturation to complex glycosylated sur- proteolysis face receptors [50]. Similar observations have been made for FGFR3 [51,52]. Spontaneous basal activity Alternative splicing and limited proteolysis may lead of RTKs appears to present an obstacle for efficient to specific changes in the domain structure of PTPs, processing and an important function of ER-bound resulting in functionally different PTP splice variants. PTPs may be suppression of this activity. It should be Among the receptor-like PTPs, alternative splicing fre- noted that RPTPs share localization in the ER with quently gives rise to structural variants of the extracel- maturing RTKs and may also participate in suppres- lular domains [9,65–68], which results in a different sion of detrimental RTK basal activity. PTPs may also profile of ligand interaction [69,70] or in the generation affect further aspects of RTK trafficking. For example, of secreted molecules which engage in alternate recycling of internalized PDGFb-receptor is enhanced ligand ⁄ receptor interactions [68,71,72]. in cells lacking T-cell PTP [53]. Alternative splicing may also result in changes in the An interesting, recently explored example of cellular regulatory domains. For example, the C-terminus of targeting is the localization of PTP-MEG2 to secretory SHP1 is extended and altered in its amino acid vesicles, where it dephosphorylates N-ethylmaleimide- sequence in SHP1-L, a long form of SHP1 generated sensitive factor and thereby regulates vesicle fusion by exon skipping [73], leading to loss of the raft-target- [54]. A Sec14-homology domain at the N-terminus of ing sequence and an essential part of the nuclear local- PTP-MEG2 ensures this localization by mediating ization sequence. In PTP-BAS, alternative splicing interactions with resident proteins, such as TIP47 [55]. affects the ligand specificity of one of the PDZ In the cytoplasm, the specificity of the interaction of domains [74]. Further, altered PTP activity may be PTPs with soluble substrates is enhanced by targeting caused by alternative splicing, as shown for SHP2 [75] domains, as exemplified by the kinase-interaction motif and recently for RPTPa [76]. Splicing events are which directs HePTP, STEP and PTPRR isoforms to regulated, and occur upon acquisition of certain members of the mitogen-activated protein kinase fam- differentiation stages or in response to growth factor ily and facilitates effective dephosphorylation [56,57]. stimulation [68,77]. Finally, PTP activity is also needed in the nucleus. At the post-translational level, many PTPs are regu- Dephosphorylation of tyrosine phosphorylated mem- lated in activity and function by limited proteolysis. bers of the STAT family is important for terminating RPTPs of the R2A family (LAR, RPTPr and RPTPd) STAT signaling, and for recycling of dephosphoryl- and the R2B-MAM family (RPTPl, RPTPj, RPTPq ated STAT molecules into the cytoplasm [58]. An and RPTPk) undergo proteolytic cleavage in the extra- important PTP in this context is TC-PTP. An ER- cellular domain by furin-like proteinases ⁄ convertases bound 48-kDa version and a 45-kDa version that can during their biogenesis, and the mature PTPs are com- shuttle into the nucleus are generated by alternative posed of non-covalently associated extracellular (E) splicing [49,59]. Nuclear localization of the 45-kDa and transmembrane–intracellular (P) domains [78,79]. TC-PTP is accomplished by a nuclear localization sig- Additional proteolysis occurs when cells are stimulated nal that is not functional in the 48-kDa isoform. The with phorbol esters or Ca2+-ionophores [80,81] or, in 45-kDa TC-PTP can effectively suppress STAT1 sig- case of MAM-domain PTPs, when cells reach high naling [60] and may also dephosphorylate STAT3 densities [13,82]. The latter leads to shedding of the [61]. SHP1 can localize to the nucleus in some cell extracellular domains and internalization and redistri-

834 FEBS Journal 275 (2008) 831–847 ª 2008 The Authors Journal compilation ª 2008 FEBS J. den Hertog et al. Regulation of protein-tyrosine phosphatases bution of the remaining PTPs [80]. Recent studies have identified further mechanistic details and suggest Glc Ox P putative functions for the shedding process in case of MAM-domain PTPs. Secondary cleavage of mature RPTPj at high cell density occurs by ADAM10, fol- lowed by a third, intra-membrane cleavage through the action of c-secretase. Interestingly, the phosphatase intracellular portion generated in this process was localized to the nucleus [82]. Recent elucidation of the crystal structure of the extracellular domain of RPTPl (see below) suggests that RPTPl is acting as a sensor Proteolysis Ubi Sumo for cell–cell contacts and is locked in cell–cell adher- ence junctions by a ‘spacer–clamp’ mechanism to regu- Fig. 3. Post-translational modification of PTPs. Most RPTPs are gly- late the tyrosine phosphorylation of other junction cosylated in their extracellular domain (Glc). PTPs are tightly regu- lated by oxidation of their catalytic-site cysteine, which inhibits components. Shedding of the extracellular domain is catalytic activity. Phosphorylation of serine, threonine and even predicted to allow truncated RPTPl to leave the junc- tyrosine residues is recognized as an important regulatory mecha- tions [83]. nism of PTPs. Proteolysis in the extracellular domain of RPTPs may Limited proteolysis is also common in non-trans- lead to shedding of the ectodomain and intracellularly to release of membrane PTPs. For example, caspase-mediated lim- the catalytically active PTP domain. Sumoylation and ubiquitination ited proteolysis of PTP-PEST has recently been linked may be important regulators of PTP stability and ⁄ or subcellular to the regulation of apoptosis [84]. Fragmentation of localization and thus of their function. PTP-PEST by caspase 3 leads to elevated PTP activity, resulting in an altered interaction between PTP-PEST CD45, PTP1B and PTP-PEST, were identified as being and adaptor molecules such as Paxillin and facilitating phosphorylated on serine residues [92–95]. However, detachment of the cell from the substratum. Notably, relatively little is known about how phosphorylation degradation of PTP-PEST upon apoptosis was rela- regulates PTPs. RPTPa is phosphorylated on two ser- tively specific and could not be seen with a range of ine residues in the juxtamembrane domain, Ser180 and other PTPs. Several PTPs, including PTP1B, PTP- Ser204 [96], and phosphorylation of these sites stimu- MEG, and SHP1 can undergo limited cleavage by cal- lates catalytic activity [97]. These two phosphorylation pain in response to an elevation in intracellular Ca2+ sites are located close to the wedge-like helix–loop– levels in platelets [85–88], leading initially to enzyme helix structure that is essential for inactivation of the activation by removing domains that exert negative dimeric conformation [98] suggesting that phosphory- regulation. Upon platelet aggregation, calpain, how- lation of these sites may lead to disruption of the inac- ever, eventually degrades completely and inactivates tive dimer conformation, thus resulting in catalytic PTP1B, a process that is critical for efficient thrombus activity. RPTPa is the major activator of Src in mitosis formation in vivo [89]. Another inactivating calpain- [99,100] and mutation of the two serine phosphoryla- dependent cleavage of PTP1B has been seen in epithe- tion sites eliminates the ability of RPTPa to activate lial cells upon UVA ⁄ B irradiation and requires Src in mitosis [101]. Whether serine phosphorylation reversible oxidation (see below) of the PTP [90]. It is affects the catalytic activity of PTP1B remains to be important to further elucidate the function of calpain determined definitively [92,102]. SHP1 and SHP2 are for regulation of PTP activity and PTP localization in phosphorylated on serine residues in response to PKC more cell types and signaling pathways. activation. SHP2 activity is not affected by serine phosphorylation [103]. Substitution of SHP1 Ser591 by Asp results in reduced catalytic activity, which led Liu Post-translational modification: et al. [104] to suggest that phosphorylation of this site phosphorylation inhibits SHP1 catalytic activity. Many PTPs are regulated by covalent post-transla- PTPs have also been found to be phosphorylated on tional modifications (Fig. 3). In general, phosphoryla- tyrosine. Tyrosine phosphorylation of PTPs immedi- tion modulates the catalytic activity of enzymes ately suggests autoregulatory or feedback mechanisms, directly by allosteric mechanisms or by providing bind- making it an intriguing regulatory mechanism for ing sites for other proteins. Phosphorylation was rec- PTPs. CD45 was found to be phosphorylated tran- ognized as a potential regulatory mechanism for PTPs siently on tyrosine [105,106]. Moreover, the SH2- early on [91] and several classical PTPs, including containing PTP, SHP2, is phosphorylated on tyrosine

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[107,108]. Tyrosine phosphorylation of SHP2 generates Table 1. Oxidation of protein-tyrosine phosphatases (PTPs). a binding site for the SH2 domain of the adaptor ROS modulator Target PTP References protein GRB2 and SHP2 thus acts as an adaptor pro- tein, linking GRB2-SOS to activated receptor tyrosine Cell-surface receptors ⁄ signaling molecules kinases [109,110]. Tyrosine phosphorylation of SHP1 Receptor tyrosine kinases and SHP2 may activate catalytic activity because sub- EGFR PTP1B [164] InsulinR PTP1B, TC-PTP [165,166] stitution of the tyrosine-phosphorylation sites by phos- PDGFR SHP2 [167] phomimetic residues led to enhanced catalytic activity T-cell receptor SHP2 [127] [111,112]. The transmembrane PTP, RPTPa is phos- B-cell receptor ‘BCR-associated PTP’ [168] phorylated on a C-terminal tyrosine [113]. This phos- Integrins ‘FAK-targeting PTP’ [169] phorylation site is a consensus GRB2-binding site and GPCRs GRB2 binds readily to phosphorylated RPTPa Lipoxin A4 SHP2 [170] [113,114]. The stoichiometry of Tyr789 phosphoryla- receptor Endothelin 1 SHP2 [171] tion is 20%, which is similar to the percentage of ROS-scavengers ⁄ reductases RPTPa bound to GRB2 [113]. This suggests that all PrxII ‘membrane-associated [129] tyrosine-phosphorylated RPTPa is bound to GRB2 PTPs’ which is not surprising in light of the autodephosph- Other orylation activity of RPTPa. Zheng et al. [99,100] UV irradiation RPTPa, RPTPj, SHP1, [90,124,172,173] developed a model in which pTyr789 binds the SH2 DEP1, PTP1B domain of Src, resulting in activation of Src by Cell density SHP2 [174] Endothelial cell PTP-PEST [128] RPTPa-mediated dephosphorylation of the inhibitory migration pTyr527 in Src. CD45 can dephosphorylate RPTPa pTyr789 in vitro and RPTPa pTyr789 is not detected in T cells that express CD45, suggesting that RPTPa is a direct substrate of CD45 [115]. The data indicate found, in addition to intermolecular Cys–Cys disulfides that there is cross-talk between RPTPs at the level of [121–123]. direct interactions, warranting further investigation Therefore, intriguing and previously unrecognized into the role of PTPs in the regulation of each other cross-talk exists between PTKs and ROS signaling and suggesting the possibility of PTP cascades, much with PTPs as mediators. Some key aspects of this like the kinase cascades identified previously. cross-talk now being explored are the specificity of the signaling, the possibility that enzymes involved in ROS metabolism control tyrosine kinase signaling and the Post-translational modification: in vivo significance of PTP oxidation. oxidation Protein-tyrosine phosphatase domains of different It is now well established that PTPs are negatively reg- PTPs display intrinsic differences with regard to sus- ulated through reversible oxidation of the catalytic-site ceptibility to oxidation. This was first demonstrated in cysteine [116,117]. Inhibitory oxidation caused by ele- analyses of RPTPa, which revealed that the second vated levels of reactive oxygen species (ROS) has been PTP domain is much more readily oxidized than the shown for various PTPs following activation of differ- catalytically more active membrane proximal PTP ent classes of cell-surface receptors, including receptor domain [124]. A large in vitro screen indicates large PTKs, integrins and G-protein-coupled receptors differences in oxidizability between PTPs that corre- (Table 1). Cell adherence and density, UV-radiation lates with the conformation of the conserved active-site and cell migration also affect levels of PTP oxidation arginine residue [125]. Similarly, the catalytic activity (Table 1). In most cases, NADPH oxidases or mito- of a panel of PTPs is differentially sensitive to oxida- chondria have been implied as the sources of ROS. tion [126]. T cells stimulated with increasing concentra-

The biochemical mechanisms of PTP oxidation have tions of H2O2 show oxidation of SHP2, but not SHP1 been elucidated in some detail. The 3D structure of [127]. Interestingly, one study also introduced the pos- reversibly oxidized PTP1B and RPTPa shows a sulfe- sibility of localized ROS signals as a mechanism for nyl-amide at the catalytic site, formed by a covalent specificity by demonstring specific oxidation of PTP- bond between the sulfur of the catalytic cysteine and PEST caused by co-localization in focal contacts with the backbone nitrogen of the neighboring serine [118– an activated NADPH oxidase [128]. 120]. Glutathionylated and nitrosylated versions of the The overall concept of PTPs as targets of ROS stim- active site cysteine of oxidized PTPs have also been ulates studies on PTP and RTK activities in cells

836 FEBS Journal 275 (2008) 831–847 ª 2008 The Authors Journal compilation ª 2008 FEBS J. den Hertog et al. Regulation of protein-tyrosine phosphatases where levels of reductases or ROS scavengers are Some of the most exciting findings showing biologi- manipulated. Deletion of peroxiredoxin II (PrxII), a cally significant PTP–ligand interactions come from peroxidase that eliminates H2O2, decreases PTP activ- recent studies of the role of PTP-LAR during synaptic ity and stimulates PDGF receptor signaling [129]. development in Drosophila. A combination of genetic Independent evidence for cell-context-dependent differ- studies, tissue culture analyses and biochemical experi- ences in PTP oxidation comes from a study showing ments led to a model where RPTP-LAR-mediated that SHP2 oxidation, following H2O2 stimulation, var- development of the neuromuscular junction is con- ies dramatically between different cell lines [130]. trolled by two heparan-sulfate proteoglycans; syndecan Recent studies support the notion that PTP oxida- and dallylike [140,141]. At the neuromuscular junction, tion is relevant in tissue settings. Restenosis, involving RPTP-LAR is expressed in the pre-synaptic neuronal PDGF receptor-dependent vascular smooth muscle part, whereas the ligands are expressed on the muscle proliferation, is enhanced in PrxII) ⁄ ) mice [129]. Fur- cells. A key substrate for RPTP-LAR in this process is thermore, systemic treatment with antioxidants in a the phospho-protein Enabled (Ena). Syndecan and dal- rabbit model of restenois attenuates lesion formation lylike both bind RPTP-LAR with high affinity but in a way that involves increased vessel-wall PTP activ- exert agonistic and antagonistic effects, respectively, on ity and reduced PDGF receptor phosphorylation [131]. the process of synaptic development. Dallylike controls Concerning PTP regulation by oxidation, it should the activity of RPTP-LAR because downregulation of be noted that Sdp1, a yeast PTP, was recently shown dallylike increases Ena phosphorylation. to be activated by oxidation [132]. Whether this mode The crystal structure of the homophilic dimer of two of regulation is also relevant for classical PTPs is likely RPTPl ectodomains provides new insight into the to be explored. However, it should be noted that the structural and mechanistic basis for earlier observa- activating oxidation-induced disulfide involves a cyste- tions on the cell-adhesive homophilic RPTPl inter- ine residue that is not conserved in classical PTPs, actions [83]. In the dimer, the two subunits occur as indicating that this mode of regulation might be two antiparallel rigid structures. The dimer structure is restricted to other subsets of PTPs. maintained through interactions between the MAM and Ig domains of one molecule and the FN1 and FN2 domains of the other. Interestingly, the length of Ligands the dimeric complex (330 A˚) is very similar to the The highly variable extracellular domains of receptor- width of the extracellular space in the adherens junc- like PTPs imply regulatory functions. As indicated in tion. This finding suggests that homophilic interactions Table 2, efforts over the last 15 years have led to the between RPTPl molecules of juxtaposed cells will pref- identification of a number of PTP ligands. Type IIB erentially occur at adherens junction, and thereby receptor PTPs, including RPTPl, RPTPj and RPTPk, restrict localization of this enzyme to its substrates in as well as type IIA RPTPd, all display homophilic cadherin complexes. Furthermore, changes in the interactions that are important in cell adhesion. width of the intracellular space following expression of RPTPb ⁄ f has multiple heterologous interaction part- different RPTPl deletion mutants indicate that this ners (Table 2) [66]. However, among these, only pleio- rigid interaction has the capacity to directly control trophin directly modulates the activity of this enzyme, the distance between cells. Finally, this structure sug- acting as an antagonist of RPTPb ⁄ f, thus increasing gests that many of the previously reported colon- the phosphorylation of a number of RPTPb ⁄ f sub- cancer-associated mutations in the related RPTPq strates including b-catenin, b-adducin, p190Rho-GAP [142] led to proteins that are either misfolded or defec- and ALK [133–136]. tive in homophilic interactions. RPTPr also has multiple binding partners, which have been identified in the nervous system and skeletal Dimerization muscles, including nucleolin, alpha-latrotoxin and the heparan-sulfate proteoglycans agrin and collagen Dimerization is a well-known regulatory mechanism of XVIII [137–139]. Characterization of the RPTPr inter- transmembrane proteins, including type I transmem- actions with these proteins demonstrates that they dis- brane proteins with a single transmembrane domain play a dependency of the dimerization state of RPTPr [143]. The first evidence that RPTPs are regulated by and that splice variants of RPTPr differ with regard dimerization was provided by chimeric proteins con- to their binding specificities [69,70,139]. The effects of sisting of the cytoplasmic domain of the RPTP, CD45, these interactions on the activity of RPTPr remain to and the extracellular domain of the EGFR [144]. This be elucidated. chimera rescues the T-cell response in cells lacking

FEBS Journal 275 (2008) 831–847 ª 2008 The Authors Journal compilation ª 2008 FEBS 837 Regulation of protein-tyrosine phosphatases J. den Hertog et al.

Table 2. Ligands of receptor protein-tyrosine phosphatases (RPTPs).

Common RPTP Effect on name class Ligand(s) activity Comments References

CD45 R1 Galectin-1 Inhibition Interaction based on recognition of [175,176] CD45 carbohydrates RPTPd R2A Homophilic binding Not reported Extracellular domain is also a ligand [177,178] promoting adhesion and neurite outgrowth LAR R2A LARFN5C Activation LAR isoform, binds homophilically [72] Laminin-Nidogen Not reported Binding is specific for a LAR splice [179] version DLAR R2A Syndecan (heparan sulfate Activation DLAR ligand [140,141] proteoglycan) Dallylike (heparan sulfate Inhibition DLAR ligand; competitive binding with [141] proteoglycan) Syndecan HmLAR2 R2A Homophilic interaction Not reported Interaction induces repulsive responses [180] (leech) in comb cells RPTPr R2A Heparan sulfate Not reported Ligand binding requires PTP dimerization [69,70,137–139] proteoglycans (agrin, collagen XVIII), nucleophilin, a-latrotoxin, unidentified ligand in developing muscle RPTPj R2B Homophilic binding Not reported [181] RPTPl R2B Homophilic binding Not reported Structure of extracellular domain reveals [83,182–184] ‘spacer–clamp’ mechanism in cell–cell adhesions; homophilic interactions appear to trigger RPTPl signaling in retial neurites RPTPk R2B Homophilic binding Not reported [185] DEP1 R3 Components in Matrigel Activation Molecular identity of ligand(s) not known [186] RPTPb ⁄ f R5 Pleiotrophin Inhibition May be linked to activation of several [133,134,136] pathways; whether inhibition occurs by induction of dimer formation is not known Tenascin Not reported [187] Contactin Not reported [188] TAG-1 ⁄ Axonin-1 Not reported [189]

CD45, indicating that the construct is functional. EGF Depending on the exact location of the cysteine treatment leads to dimerization of the chimera and residue, these dimers are active or inactive [146]. Muta- functionally inactivates the chimera, in that the T-cell tion of the wedge in the inactive mutant leads to acti- response is impaired after EGF treatment. The crystal vation of PTP activity, demonstrating the importance structure of the membrane-proximal domain of RPTPa of the wedge in dimerization-induced inactivation of provided evidence for dimerization-induced inactiva- RPTPs. Moreover, peptides encompassing the wedge tion of RPTPs [98]. Dimers were observed in these of LAR or RPTPl bind these RPTPs in a homophilic crystals with a large buried surface at the interface of manner and administration of these peptides to cells the two molecules. A helix–loop–helix, wedge-like results in specific defects that are consistent with the structure of one of the molecules inserted into the cat- inhibition of RPTP function [147]. Although the wedge alytic cleft of the other and vice versa, thereby occlud- is conserved among RPTPs and functional experiments ing access for substrates to the catalytic site and suggest that it has an important role in dimerization- inactivating PTP. Mutation of the wedge in the induced inactivation, the model of wedge-mediated EGFR–CD45 chimera abolishes EGF-induced func- RPTP inactivation is the subject of debate because the tional inactivation of the chimera, indicating that the crystal structures of full-length LAR and full-length wedge has an important role in the dimerization- CD45 are not compatible with this role for the wedge induced inactivation of RPTPs [145]. Introduction of a [148,149]. The membrane-distal PTP domain causes a cysteine residue into the extracellular juxtamembrane steric clash when the wedge of one monomer is mod- domain of RPTPa leads to constitutive dimerization. eled into the catalytic site of the other, as observed in

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RPTPa. However, if one assumes that there is flexibil- ity between D1 and D2, a wedge–catalytic site interac- Ligands tion is feasible in CD45 and LAR. Flexibility between D1s and D2s may be regulated dynamically, thus con- trolling the formation of inactive RPTP dimers. The functional data show that RPTPs can be regu- lated by dimerization. But do RPTPs dimerize? There is ample evidence that RPTPs dimerize in living cells. Chemical cross-linkers show dimerization of CD45, Post-translational RPTPa, Sap-1 and RPTPr [70,150–153]. RPTPa ho- modification modimerizes in living cells, as demonstrated by fluores- cence resonance energy transfer between chimeras of RPTPa proteins fused to derivatives of green fluores- cent protein [154]. Chin et al. [155] showed that dimer- ization of many RPTPs may be driven by their transmembrane domain. PTP domains may also be involved in homo- and heterodimerization [151,156,157]. Co-immunoprecipitation experiments have been used to demonstrate dimerization of full- Active Inactive length RPTPa [150], CD45 [158] and RPTPe [159]. Although dimerization was first shown to inactivate Fig. 4. Rotational coupling regulates RPTP dimers. RPTPs dimerize RPTPs, it is now evident that both active and inactive constitutively. Whether RPTP dimers are active depends on the RPTP dimers exist. The exact make-up of the dimers exact make-up of the dimers. Post-translational modifications, such determines the catalytic activity of the RPTPs. RPTPa as oxidation or phosphorylation may shift the dimers from an active mutants with disulfide bonds at different positions in to an inactive state or vice versa by inducing subtle changes in rota- tional coupling. The dimeric states may be stabilized by different the extracellular juxtamembrane domain suggest that ligands binding to either form of the extracellular dimer. Ligand subtle changes in the relative orientation of the RPTPs binding may therefore drive the equilibrium of dimers into one of determines whether they are active or inactive and the forms, representing classical outside-in signaling. Alternatively, actually provides an appealing model for regulation. intracellular post-translational modifications may change the Changes in the experimental conditions lead to subtle exposed surface of the extracellular domain, resulting in binding of changes in the quaternary structure of RPTPa, as dem- different ligands, which represents inside-out signaling. onstrated using an epitope tag in the extracellular domain of RPTPa [160]. Rotational coupling within RPTPs may therefore be an important regulatory scriptional and translational control is likely to reveal mechanism (Fig. 4). As described above, Lee et al. [70] novel processes governed by PTPs. It should also be demonstrated that only dimeric ectodomains of noted that the involvement of microRNAs in control- RPTPr bind ligand and that subtle changes in the ling PTP expression remains to be explored. rotational coupling of the ectodomains abolished Recent discoveries of regulatory ligands for Dro- ligand binding. These results provide support for the sophila RPTP-LAR should encourage the continued model that intracellular changes, such as phosphoryla- search for additional PTP ligands. It will be interesting tion or oxidation, result in changes in the quaternary to follow-up on the concept of inside-out signaling and conformation within RPTP dimers, thus altering the to further analyze how oxidation and dimerization ligand-binding properties. Therefore, RPTPs may not affect ligand binding. The structural understanding of only have the capacity for outside-in signaling, i.e. to the RPTPl homophilic interactions will assist in stud- bind ligands extracellularly resulting in changes in cat- ies on whether this type of binding affects the specific alytic activity intracellularly, but also for inside-out activity of RPTPs involved in cell-adhesive inter- signaling, i.e. to alter the ligand binding repertoire in actions. response to intracellular changes. To date, studies on post-translational PTP modifica- tions have focused on reversible oxidation of the active site and phosphorylation. However, other types of Outlook modifications are also involved in controlling PTPs. Control of PTP expression levels remains surprisingly PTP1B is sumoylated in a manner that inhibits its cat- poorly characterized. Improved understanding of tran- alytic activity [161]. It will be interesting to see if other

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PTPs are regulated by sumoylation. Likewise, ubiquiti- T (2004) Protein tyrosine phosphatases in the human nation may regulate the stability and activity of PTPs, genome. Cell 117, 699–711. warranting further investigation. 2 Andersen JN, Jansen PG, Echwald SM, Mortensen Further studies on the regulation of PTPs by oxida- OH, Fukada T, Del Vecchio R, Tonks NK & Moller tion will continue to give new insights into fundamen- NP (2004) A genomic perspective on protein tyrosine tal cell processes. One key topic where progress can be phosphatases: gene structure, pseudogenes, and genetic expected is the source of ROS involved in PTP regula- disease linkage. FASEB J 18, 8–30. tion. Analyses of whether spatially restricted ROS 3 Neel BG, Gu H & Pao L (2003) The ‘Shp’ing news: production is a common mechanism for conferring SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci 28, 284–293. specificity are also awaited. 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Finally, it may be possible to exploit the 26511. reversible oxidation of PTPs for therapeutic purposes, 9 Ogata M, Sawada M, Kosugi A & Hamaoka T (1994) as indicated by early studies with non-specific antioxi- Developmentally regulated expression of a murine dants [131]. It has also been speculated that modifiers receptor-type protein tyrosine phosphatase in the thy- that stabilize the inhibited oxidized conformation of mus. J Immunol 153, 4478–4487. 10 Taniguchi Y, London R, Schinkmann K, Jiang S & the active site could be designed. Hopefully, continued Avraham H (1999) The receptor protein tyrosine phos- collaborative studies will thus be able to combine the phatase, PTP-RO, is upregulated during megakaryo- knowledge derived from basic biology studies on PTPs, cyte differentiation and Is associated with the c-Kit with analyses of the molecular etiology of human dis- receptor. 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