Abstract
In higher eukaryotes, the Tyr phosphorylation status of cellular proteins results from the coordinated action of Protein Tyrosine Kinases (PTKs) and Protein Tyrosine Phosphatases (PTPs). PTPs have emerged as highly regulated enzymes with diverse substrate specificity, and proteins with Tyr-dephosphorylation or Tyr-dephosphorylation-like properties can be clustered as the PTPome. This includes proteins from the PTP superfamily, which display a Cys-based catalytic mechanism, as well as enzymes from other gene families (Asp-based phosphatases, His-based phosphatases) that have converged in protein Tyr-dephosphorylation-related functions by using non-Cys-based catalytic mechanisms. Within the Cys-based members of the PTPome, classical PTPs dephosphorylate specific phosphoTyr (pTyr) residues from protein substrates, whereas VH1-like dual-specificity PTPs dephosphorylate pTyr, pSer, and pThr residues, as well as nonproteinaceous substrates, including phosphoinositides and phosphorylated carbohydrates. In addition, several PTPs have impaired catalytic activity as a result of amino acid substitutions at their active sites, but retain regulatory functions related with pTyr signaling. As a result of their relevant biological activity, many PTPs are linked to human disease, including cancer, neurodevelopmental, and metabolic diseases, making these proteins important drug targets and molecular markers in the clinic. Here, a brief overview on the biochemistry and physiology of the different groups of proteins that belong to the mammalian PTPome is presented.
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Key words
- Tyrosine phosphatase
- Lipid phosphatase
- Asp-phosphatase
- His-based phosphatase
- Phosphorylation
- Dephosphorylation
1 Tyr Phosphatases: Positive and Negative Protein Regulators of Cell Signaling
Tyr phosphorylation /dephosphorylation is a profuse regulatory mechanism of the responses of the cells to physiologic and pathologic changes in their environment, and it is exerted in holozoan organisms by the coordinated action of Protein Tyrosine Kinases (PTKs) and Protein Tyrosine Phosphatases (PTPs) [1, 2]. Unlike protein kinases, PTPs have evolved independently of the Ser/Thr Phosphatases, displaying a characteristic PTP domain, a CxxxxxR conserved catalytic loop (where C is the catalytic Cys, x is any amino acid, and R is an Arg), and a Cys-based catalysis [1, 3–7]. Beyond that, the mammalian PTPome , considered as the cluster of proteins with Tyr-dephosphorylation or Tyr-dephosphorylation-like activity, includes proteins distributed in several families (Cys-based, His-based, Asp-based), among which the PTP family itself contributes with most of the members. In line with this, we have defined the concept of an open and extended PTPome whose members fulfill the following criteria: (a) harboring of a structurally defined PTP domain; or (b) presence of a CxxxxxR signature catalytic motif within a non-PTP phosphatase domain; or (c) displaying experimentally validated Tyr phosphatase activity; or (d) displaying high sequence similarity to members with demonstrated Tyr phosphatase activity . This updated human PTPome contains 125 genes, which encode both catalytically active and inactive (pseudophosphatases ) proteins [8] (Fig. 1 and Table 1).
Although Tyr phosphatases were initially considered cell signaling shutting-off enzymes, it is now widely known that Tyr phosphatases work both as positive and negative regulators of cell signaling, switching on and off with high specificity the biological activity of signal transduction molecules. Early after the first report of the amino acid sequence of a PTP in 1988 [9], findings of Tyr phosphatases working as positive signaling regulators followed and PTPRC/CD45 was shown to be essential for activation of the Src-family kinase (SFK) Lck in T lymphocytes, by virtue of dephosphorylation of its inactivating C-terminal Tyr residue [10, 11]. Later on, PTPRA/RPTPα overexpression was reported to cause cell transformation of rat embryo fibroblasts, in association with dephosphorylation and activation of Src [12]. In fact, several PTPs are bona fide positive regulators of SFKs by specific Tyr dephosphorylation [13]. A classic example of targeted negative regulation of cell signaling by Tyr phosphatases is that of the kinase interaction motif (KIM)-containing MAPK-PTPs (PTPRR, PTPN5, and PTPN7), which specifically dephosphorylate the activating Tyr residue in the catalytic loop of MAPKs upon KIM-mediated binding [14, 15]. Thus, Tyr phosphatases may display exquisite substrate specificity and drive distinct signal outputs in coordination with specific TKs, as it has been recently illustrated in the case of PTPN1/PTP1B [16]. Some other examples of the positive and negative role of Tyr phosphatases in cell signaling, using EGFR-mediated signaling as a paradigm, are schematically depicted in Fig. 2.
Next, a brief account of the properties of Tyr phosphatases, as exemplified by the mammalian PTPome members, is presented.
2 Classification of Tyr Phosphatases
Here, we will follow the classification of PTPs by Alonso et al. [3], updated according to Alonso et al. [8] (Fig. 1 and Table 1). As shown, most of the PTPome members (116 genes) are Cys-based Tyr phosphatases, although many of those do not have pTyr as their physiologic substrate but rather phosphoinositides (PIPs). The rest includes the EYAs Asp-based (four genes) and the His-based (five genes) Tyr phosphatases.
3 Class I Cys-Based Phosphatases
Class I of Tyr phosphatases includes most of the Tyr phosphatases identified so far in the human genome. Over 100 phosphatases form part of this group of enzymes, characterized by a similar topology, the presence of common essential catalytic residues and a similar catalytic mechanism [7]. In our classification, six major groups can be differentiated in this class: classical PTPs (subclass I.I), VH1-like/DUSPs (subclass I.II), SACs (subclass I.III), Paladin (subclass I.IV), INPP4s (subclass I.V), and TMEM55s (subclass I.VI) phosphatases.
3.1 Classical PTPs
The most homogeneous group is that of classical PTPs. Alignments of their primary sequence and determination of the structures of the PTP domains (about 250 amino acids in length) from most of the classical Tyr phosphatases have allowed the identification of structural motifs conserved in this family and their implication in catalysis and physiological function [17, 18]. Classical PTPs are pTyr specific enzymes. This pTyr specificity is due to a loop present in classical PTPs structure and named pTyr loop that deepens the active site and impedes access of pSer/Thr to the catalytic Cys. In spite of this, the classical PTPs PTPRN2 and PTPRQ dephosphorylate phosphoinositides. This group is further divided into receptor and non-receptor phosphatases. Apart from the presence of a transmembrane domain that localizes the receptor enzymes in the plasma membrane, 13 out of 20 of these phosphatases contain two PTP domains. The domain close to the membrane, named D1, harbors the catalytic activity, while the second domain, D2, is mostly inactive and its function seems to be regulatory. D2 domains in RPTPs show a high degree of sequence conservation, indicating a conserved function through evolution [19]. Despite presenting receptor-like extracellular domains, ligands have only been identified in some cases. For instance, PTPRK/RPTPκ, PTPRM/RPTPμ, PTPRU, and PTPRT interact by homotypic interactions, which seem to be involved in cell-cell adhesion processes that limit cell growth. On the other hand, the proteolysis of these PTPs generates extracellular and intracellular independent domains, which have been proposed as important mediators of oncogenicity [20, 21]. Other RPTPs , such as PTPRD/RPTPδ, PTPRF/LAR, and PTPRS/RPTPσ, bind membrane-bound ligands on adjacent cells and orchestrate cell signaling at specific cell compartments, like the synaptic junctions [22, 23]. In this regard, heparan sulfate proteoglycans (HSPGs) bind to PTPRF increasing its phosphatase activity, while another ligand , the protein Dallylike, inhibits its activity, regulating the function of this phosphatase in the formation of synapses [24]. Sugar components from PTPRC/CD45 bind to the endogenous lectin Galectin-1, which reduces PTPRC phosphatase activity and facilitates T cell death during thymic maturation [25, 26]. Remarkably, binding of Galectin-3 to PTPRC from B cells also diminishes PTPRC phosphatase activity , but conferring resistance to apoptosis-inducing agents [27], illustrating the cell type-dependent tuned specificity of the biological activity of PTPs. Another interesting example is that of PTPRZ1 /RPTPζ, which binds to pleiotrophin and contactins. Binding to the cytokine pleiotrophin leads to a decrease in its phosphatase activity , and to an increase in Tyr phosphorylation of β-catenin and the ALK TK receptor [28, 29].
Non-receptor classical PTPs are 17 phosphatases which in addition to the PTP domain present additional regulatory and targeting domains and motifs. Some of these domains (FERM, BRO1, FYVE, or C2) are involved in binding to lipids in cellular membranes. Other domains, like the SH2 domain present in PTPN6/SHP1 and PTPN11/SHP2, regulate the activity of the phosphatase, whereas Pro-rich motifs permit the interaction with SH3 or F-BAR domains [30, 31]. As mentioned above, by virtue of these protein-interaction motifs and domains, as well as by intrinsic specificity for substrate recognition in the catalytic domains, PTPs show a physiologically well-tuned substrate specificity that exerts both positive and negative inputs in cell signaling pathways (Fig. 2).
3.2 VH1-Like/Dual-Specificity Phosphatases (DUSPs)
VH1-like/DUSP PTPs are more diverse than classical PTPs and present a phosphatase domain much smaller, usually 100 amino acids shorter. The first phosphatase of this group was identified in the vaccinia poxvirus and was named VH1 [32]. Then many others were identified up to the 64 genes that are included in this group in the human genome. The phosphatases in this group show a great diversity of substrates, from RNA to lipids, and include pTyr , pSer , and pThr phosphatases. Several groups can be distinguished among VH1-like phosphatases [3, 8]. Among them, the ten active MAP kinase (MAPK) phosphatases (MKPs), which target with great specificity MAPKs thanks to the presence of specific binding domains, are major players in the regulation of cell growth, survival, and differentiation [33, 34]. Myotubularins (MTMs) dephosphorylate PI(3)P and PI(3,5)P2 to produce PtdIns(5)P, and constitute an important VH1-like/DUSP subfamily, with nine phosphatase-active and six phosphatase-inactive members (Table 1). They regulate endocytosis and membrane and vesicle trafficking, and have been genetically linked with human myopathies and neuropathies [35, 36]. A major human disease-related enzyme which belongs to the VH1-like/DUSP phosphatases is the PTEN tumor suppressor, which targets as the major substrate the PI(3,4,5)P3 product of the oncogenic PI3K. PTEN is a physiologic homeostatic regulator whose involvement in human disease goes beyond cancer [36]. Interestingly, some VH1-like/DUSP phosphatases are the lowest expression of a phosphatase, being almost exclusively a PTP domain of around 150 amino acids, like DUSP23/VHZ [37]. Some of these small phosphatases also dephosphorylate MAPKs , like DUSP3 / VHR [38, 39].
3.3 SAC Phosphatases
The SAC phosphoinositide phosphatases have in common the presence of a SAC catalytic domain, whose core is topologically similar to that of the PTP catalytic domain of some VH1-like/DUSPs and contains a CxxxxxR catalytic motif [40]. The SAC enzymes included in the human PTPome display substrate specificity towards mono- and multi-phosphorylated PIPs, and form part of two subgroups: SACML1/SAC1, INPP5F/SAC2, and FIG4/SAC3, which possess the SAC domain as the only catalytic domain; and SYNJ1/Synaptojanin 1 and SYNJ2/Synaptojanin 2, which possess a non-Cys-based Mg2+-dependent 5-phosphatase domain in addition to the SAC domain [41–44].
3.4 Paladin
Paladin/PALD1 is a protein that presents two putative PTP domains that contain the signature motif CxxxxxR. However, no phosphatase activity has been demonstrated yet for Paladin [45]. The phosphatase domains of Paladin belong to the PTP-like phytase (PTP-LP) type. Phytases are phosphatases that hydrolyze phosphate from myo-inositol hexakisphosphate, also called phytate [46], and they are found in different families of enzymes: histidine acid phosphatases, β-propeller phytases, purple acid phosphatases, and PTP-like phytases [46, 47]. PTP-LPs are found in anaerobic bacteria in ruminants [48], and in some human pathogens, such as Clostridium botulinum. The phytase domain from Selenomonas ruminantium (PhyAsr) has been crystallized, showing a similar topology to VH1-like phosphatases [49], with a PTP-loop that contains the catalytic Cys. Paladin expression is regulated during embryonic development [50–52] and it has been implicated in vascular biology [53]. A mouse knockout has been generated, but no phenotype has been reported for the loss of expression of this gene [53]. Paladin has also been involved in the regulation of insulin signaling [45].
3.5 INPP4 and TMEM55 Phosphatases
These two groups of Cys-based phosphatases have been recently added to the PTPome based on the presence on their four members of a conserved CxxxxxR motif (Tables 1 and 2) and phosphatase activity towards inositol polyphosphates and phosphoinositides [8].
INPP4A and INPP4B are two related enzymes that dephosphorylate the D4 position from PI(3,4)P2, Ins(3,4)P3, and Ins(1,3,4)P2. By virtue of their relative specificity towards PI(3,4)P2, INPP4A and INPP4B are involved in the negative regulation of PI3K -mediated signaling and AKT activation [54–56]. INPP4A has been related with Huntington’s disease because of its involvement in the control of excitotoxic cerebellar- and striatum-neuronal cell death [57, 58], as well as with the regulation of platelet aggregation and asthma-related inflammation [59–61]. INPP4B exerts tumor suppressor activities in different human cancers by both PI3K /AKT-dependent and -independent mechanisms [56, 62–65]. In addition, INPP4B has been related with osteoporosis by its negative regulatory role on osteoclast differentiation [66].
TMEM55A and TMEM55B are two small phosphoinositide phosphatases that dephosphorylate the D4 position of PI(4,5)P2 [67]. TMEM55A and TMEM55B regulate EGFR lysosomal degradation [67], and a role for TMEM55B in p53 stabilization of nuclear p53 has also been reported [68].
4 Class II Cys-Based Phosphatases
The Class II of Cys-based PTPs now includes two phosphatases, the former member LMW-PTP/ACP1, and the new addition Ssu72 (suppressor of Sua72), which has been added to this family due to its structural homology with LMW-PTP [69]. LMW-PTP has been studied for many years and it has been linked with diseases related with the immune response, inflammation, and cancer [70, 71]. However, the physiological role of this phosphatase is still poorly defined. LMW-PTP and Ssu72 present the typical PTP CxxxxxR signature motif at the N-terminus of the PTP domain, and the Asp acid involved in catalysis is C-terminal, more than 100 amino acids away in the primary sequence, in contrast with Class I PTPs, where precedes the signature motif . LMW-PTP and Ssu72 are evolutionarily related to bacterial arsenate-reductases coupled to thioredoxin, which present the PTP CxxxxxR signature motif and display the same topology [72, 73]. Unlike LMW-PTP, which is specific for pTyr , Ssu72 dephosphorylates specifically pSer5 and pSer7 in the C-terminal domain (CTD) of RNA polymerase II [74–76], and thus Ssu72 is involved in mRNA processing. Ssu72 has also been recently involved in sister chromatid segregation during cell division [77] through the regulation of the cohesin protein complex [78].
5 Class III Cys-Based Phosphatases
This class contains three members, cell division cycle (CDC) 25A, B, and C (CDC25A, CDC25B, and CDC25C), which activate CDKs by dephosphorylating Thr14 and Tyr15 in the ATP binding loop of CDKs [79]. Thus, CDC25 phosphatases are involved in cell-cycle progression and in the checkpoint pathways that control DNA damage response [80]. This family has expanded through evolution from a single gene in yeast to three genes in mammals. The catalytic domain of CDC25 is a Rhodanese domain [81, 82], which was first found in a sulfurtransferase called rhodanese [83]. This domain presents an ample distribution in living organisms, being present in Eukarya, Archaea, and Eubacteria. An inactive rhodanese domain, named CDC25 homology domain (CH2), in which the catalytic Cys is replaced by another amino acid, is present in MKPs [84]. This CH2 domain includes a kinase interaction motif (KIM) involved in binding to MKPs [14, 85]. CDC25s present an extended catalytic loop. Whereas other rhodanese enzymes present four amino acids between the catalytic Cys and Arg, CDC25s contain five amino acids by insertion of one extra residue, to generate the signature motif of Cys-based PTPs. The addition of this extra amino acid seems to change the enzyme activity from a sulfur transfer reaction to phosphate hydrolysis [86]. This family lacks a WPD loop containing the general acid/base that works in the second step of the catalysis in Classes I and II. In this sense, it has been proposed that, in CDC25 phosphatases, the initial proton donor is the monoprotonated phosphate that acts as its substrate in lieu of the bisanionic phosphate used by Class I PTPs. An invariant Glu, placed in the CDC25s PTP-loop contiguous to the catalytic Cys, has been proposed to be involved in the catalysis [87, 88].
6 Asp-Based Phosphatases
Among the members of the large family of Asp-based phosphatases, aka Haloacid Dehalogenase (HAD) phosphatases, there are a few that possess Tyr phosphatase activity [89]. We refer to the four members of the Eyes absent (EYA) family of transcription factors, which are involved in the formation of many tissues and organs [90]. They contain a poorly conserved N-terminal domain, responsible for its transactivation activity [91], and a highly conserved C-terminal domain, called EYA domain, that participates in protein interactions, mainly with the Six family proteins, and through these interactions, in DNA binding [92]. EYA domain shares the active core of the HAD phosphatases and presents Tyr phosphatase activity [93–95]. EYA proteins also have Thr phosphatase activity , but this activity is catalyzed by other active sites located in the N-terminal domain and not related to HAD phosphatase activity [96, 97]. Hence, EYA proteins have a dual specificity that is based on two separated catalytic domains that probably act on different substrates. The only avowed substrate for the Tyr phosphatase activity of EYA proteins is the histone H2AX [98, 99], whereas no substrate for the Thr phosphatase activity has been discovered.
7 His-Based Phosphatases
The His phosphatase (HP) superfamily includes numerous enzymes that dephosphorylate a great variety of substrates, from proteins to small molecules involved in metabolism [100]. Two branches are distinguished in this family. Branch one is called PGM (phosphoglycerate mutase) group, because the enzyme Diphosphoglycerate mutase (dPGM) is here included. The second branch is termed AP (acid phosphatases). The PGM subfamily is better represented in prokaryotes, while the AP subfamily is more abundant in eukaryotic organisms. Tyr phosphatases have been identified in both subfamilies, UBASH3 phosphatases in the PGM branch and some acid phosphatases in the second branch [8].
The UBASH3 (Ubiquitin-associated and SH3 domain-containing protein) group of phosphatases includes UBASH3A and UBASH3B [101–104]. UBASH3 proteins contain an N-terminal UBA (ubiquitin-associated) domain, an SH3 (Src homology 3) domain, and a phosphatase domain similar to the PGM branch of the His phosphatases . The UBA domain interacts with ubiquitin and ubiquitylated proteins, including UBASH3 phosphatases [101, 103, 105]. The PGM domain, in addition to phosphatase activity , allows dimerization of these phosphatases. Expression of UBASH3B is ubiquitous, while UBASH3A expression is restricted to lymphocytes [103, 106]. The phosphatase activity of UBASH3B is much higher than UBASH3A [107–109].
UBASH3A and UBASH3B Tyr phosphatases dephosphorylate ZAP70 and Syk Tyr kinases [106, 109–111] with exquisite specificity, as they just dephosphorylate a few Tyr in these kinases [107, 109, 111, 112]. UBASH3B has also been implicated in dephosphorylation of the EGFR, where it also targets specific Tyr [112].
UBASH3 phosphatases can work both as negative or positive regulators. In the immune system, they seem to function as negative regulators, mainly through the regulation of immunoreceptor tyrosine-based activation motif (ITAM) associated receptors, such as TCR and FcεR. Identification of several SNPs associated with autoimmune diseases in these phosphatases further supports their relevance in the immune system [113]. On the other hand, it has been found that UBASH3B works as positive regulator of EGFR. Upon EGFR stimulation, UBASH3B is recruited to the EGFR through the interaction with the E3 ubiquitin ligase CBL [101, 103]. UBASH3 SH3 domain binds to the central Pro-rich region of CBL [101, 103], and this complex dephosphorylates EGFR and inhibits its subsequent degradation, which is dependent on EGFR ubiquitination by CBL. In this sense, it has been found that UBASH3 is overexpressed in triple negative breast cancer (TNBC), as well as in prostate cancer cells [114]. UBASH3B is involved in tumor growth and metastasis mainly by inhibiting EGFR degradation, and for this reason it seems that UBASH3B could behave as an oncogenic phosphatase in TNBC.
The group of His-based acid phosphatases related with Tyr dephosphorylation includes ACPP/PAP, ACP2/LAP, and ACPT (Table 1). They dephosphorylate small organic nonproteinaceous moieties, as well as pTyr from peptides and proteins [115]. In particular, ACPP and ACPT have been associated with Tyr dephosphorylation and inactivation of distinct members of the EGFR family [116–118]. ACPP, which is abundant in prostate tissue, has been proposed as a tumor suppressor for prostate cancer [119, 120].
8 Catalytic Mechanism of Tyr Phosphatases
Hydrolysis of phosphate from Tyr-phosphorylated proteins is initiated by a nucleophilic attack. The nucleophile that starts the reaction is different in each family of PTPs: Cys in Cys-based phosphatases, Asp in Eya HAD, and His in HPs [3, 115, 121]. The catalytic mechanism for Cys, Asp, and His phosphatases has been well established and involves two steps. The reaction is initiated by a nucleophilic attack carried out by the catalytic amino acids, Cys, Asp, or His. A phospho-enzyme intermediate is formed and the dephosphorylated substrate is released. In addition to the catalytic residue that starts the nucleophilic attack, in the first step of the reaction, an Asp participates donating a proton to the tyrosyl leaving group of the substrate. Next, in the second step of the reaction, the phosphate is released and the phosphatase is regenerated. In this step, a water molecule acting as nucleophile breaks the phospho-enzyme intermediate. This molecule of water is deprotonated by an Asp, which is the same that intervened as a general acid in the first step of the reaction, and now works as a general base (Fig. 3). Representative catalytic signature motifs from the distinct groups of Cys-based Tyr phosphatases are shown in Table 2. Note that these groups can be classified, at least in part, based on the sequence of this motif.
The correct orientation of the phosphate for catalysis as well as the stabilization of the transition state during the reaction is mediated by the Arg present in the catalytic pocket at the end of the P-loop, which is part of the signature motif (CxxxxxR) in the Cys-based PTPs. In HPs, the function of this Arg in Cys-based phosphatases seems to be mediated by two Arg and a His within the catalytic pocket, which together with the catalytic His form the quartet of residues conserved in all HPs. On the other hand, HAD phosphatases use an Asp as the catalytic residue and Mg2+ as a cofactor to stabilize the transition state (Table 2) [122].
In contrast to the diversity found in the initial nucleophile in these families of phosphatases, they have adopted an Asp as the general acid/base. Nevertheless, in UBASH3 phosphatases, HPs of the PGM branch, it seems that a Glu develops this function [107, 123]. In most of the Cys-based PTPs, the general acid/base Asp is usually located in an additional loop in the active site. In Class I PTPs this Asp precedes by 30–40 amino acids the P-loop that contains the Cys. This loop contains a conserved stretch of amino acids, WPD, in classical PTPs that is used to name this loop as WPD loop. However, these residues are not conserved outside this group of phosphatases. On the other hand, in Class II the Asp-loop is 100 amino acids C-terminal to the catalytic Cys. Interestingly, it has been suggested than in Class III phosphatases a Glu in the P-loop develops this function [87, 88], as well as in Myotubularins [36]. Similarly, in the EYAs HADs, the Asp is found in the same loop that the catalytic Asp at a +2 position (Table 2) [121].
9 The PTPome in Model Organisms
PTPome human and mouse genes are well conserved, with the exception of PTPRV/Ptprv, which is a transcribed pseudogene in human and a normal gene in mouse [124]. In addition, the two human TPTE and TPTE2 genes are represented with one single gene in mouse [125]. Dario rerio (zebrafish ) and Drosophila melanogaster (fruit fly), two widely used metazoan model organisms, contain members from all Tyr phosphatase families. Within the group of classical PTPs, D. rerio ortholog genes to all the mammalian PTPs have been found, with the exception of PTPN7, PTPN12, and PTPN14. In addition, at least 14 classical PTP genes are duplicated in D. rerio [126, 127]. In the case of D. melanogaster, the representation of Cys-based phosphatases covers about half of the human Cys-based phosphatase genes, with all the D. melanogaster Tyr phosphatases having orthologs in humans [127, 128]. The PTPome of the yeast Saccharomyces cerevisiae (budding yeast ), the more used experimental model from Fungi kingdom, is mostly composed of Tyr-specific and dual-specificity Cys-based phosphatases dedicated to MAPKs dephosphorylation , as well as of dual-specificity phosphatases of unknown function [127, 129, 130]. Two SAC members are present in S. cerevisiae [131], as well as Ssu72 [75].
10 Conclusion and Future Perspectives
A variety of mammalian phosphatases from different gene families (PTPome) dephosphorylate pTyr residues or show topological similarity in their catalytic domains with the canonical PTP domain. This has been used to establish classifications and evolutionary relationships between these enzymes [3–6, 132, 133]. We have summarized here our concept of an open and extended PTPome which includes proteins that: (a) harbor a structurally defined PTP domain; or (b) contain a CxxxxxR signature catalytic motif within a non-PTP phosphatase domain; or (c) display experimentally validated Tyr phosphatase activity ; or (d) display high sequence similarity to members with demonstrated Tyr phosphatase activity . The relative conservation of Tyr phosphatase functions in distant Phyla, and the evolutionary convergence of several PTPome members towards Tyr- or PIP-dephosphorylation , outlines the physiologic importance of such functions. In this regard, bacteria and protozoan parasite Tyr phosphatases have a pathogenic role in several infectious diseases, which make them direct drug targets for therapeutic intervention [134–136]. Moreover, Tyr phosphatases have direct roles in the etiology of many hereditary and nonhereditary human diseases, including cancer, neurodegenerative, metabolic, immune, and heart diseases [33, 136–152]. The dual role of many of the Tyr phosphatases in relation with human disease constitutes both a challenge and an open scenario for the implementation of therapies based on these enzymes. For instance, many classical PTPs display pro-oncogenic or anti-oncogenic roles depending on the tissue and the physiologic context [134, 135, 140, 144]. A clinically relevant example is the lipid phosphatase PTEN , whose reconstitution, activation, or delivery could be beneficial in cancer therapy , whereas its inhibition could be beneficial in the treatment of neuroregeneration-related diseases [153–156]. The feasibility of Tyr phosphatases as both potential targets for inhibition and active drugs in human disease therapy will be under dedicated scrutiny in the upcoming future.
References
Tonks NK (2013) Protein tyrosine phosphatases—from housekeeping enzymes to master regulators of signal transduction. FEBS J 280:346–378
Hunter T (2014) The genesis of tyrosine phosphorylation. Cold Spring Harb Perspect Biol 6:a020644
Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T (2004) Protein tyrosine phosphatases in the human genome. Cell 117:699–711
Andersen JN, Jansen PG, Echwald SM, Mortensen OH, Fukada T, Del Vecchio R, Tonks NK, Moller NP (2004) A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB J 18:8–30
Li X, Wilmanns M, Thornton J, Kohn M (2013) Elucidating human phosphatase-substrate networks. Sci Signal 6:rs10
Hatzihristidis T, Liu S, Pryszcz L, Hutchins AP, Gabaldon T, Tremblay ML, Miranda-Saavedra D (2014) PTP-central: a comprehensive resource of protein tyrosine phosphatases in eukaryotic genomes. Methods (San Diego, Calif) 65:156–164
Tautz L, Critton DA, Grotegut S (2013) Protein tyrosine phosphatases: structure, function, and implication in human disease. Methods Mol Biol (Clifton, NJ) 1053:179–221
Alonso A, Pulido R (2016) The extended human PTPome: a growing tyrosine phosphatase family. FEBS J 283:1404–1429
Charbonneau H, Tonks NK, Walsh KA, Fischer EH (1988) The leukocyte common antigen (CD45): a putative receptor-linked protein tyrosine phosphatase. Proc Natl Acad Sci U S A 85:7182–7186
Mustelin T, Coggeshall KM, Altman A (1989) Rapid activation of the T-cell tyrosine protein kinase pp56lck by the CD45 phosphotyrosine phosphatase. Proc Natl Acad Sci U S A 86:|6302–6306
Ostergaard HL, Shackelford DA, Hurley TR, Johnson P, Hyman R, Sefton BM, Trowbridge IS (1989) Expression of CD45 alters phosphorylation of the lck-encoded tyrosine protein kinase in murine lymphoma T-cell lines. Proc Natl Acad Sci U S A 86:8959–8963
Zheng XM, Wang Y, Pallen CJ (1992) Cell transformation and activation of pp60c-src by overexpression of a protein tyrosine phosphatase. Nature 359:336–339
Roskoski R Jr (2005) Src kinase regulation by phosphorylation and dephosphorylation. Biochem Biophys Res Commun 331:1–14
Pulido R, Zuniga A, Ullrich A (1998) PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. EMBO J 17:7337–7350
Saxena M, Williams S, Brockdorff J, Gilman J, Mustelin T (1999) Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). J Biol Chem 274:11693–11700
Fan G, Aleem S, Yang M, Miller WT, Tonks NK (2015) Protein tyrosine phosphatase and kinase specificity in regulation of SRC and BRK. J Biol Chem 290(26):15934–15947
Andersen JN, Mortensen OH, Peters GH, Drake PG, Iversen LF, Olsen OH, Jansen PG, Andersen HS, Tonks NK, Moller NP (2001) Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol Cell Biol 21:7117–7136
Barr AJ, Ugochukwu E, Lee WH, King ON, Filippakopoulos P, Alfano I, Savitsky P, Burgess-Brown NA, Muller S, Knapp S (2009) Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell 136:352–363
Ahuja LG, Gopal B (2014) Bi-domain protein tyrosine phosphatases reveal an evolutionary adaptation to optimize signal transduction. Antioxid Redox Signal 20:2141–2159
Mohebiany AN, Nikolaienko RM, Bouyain S, Harroch S (2013) Receptor-type tyrosine phosphatase ligands: looking for the needle in the haystack. FEBS J 280:388–400
Craig SE, Brady-Kalnay SM (2015) Regulation of development and cancer by the R2B subfamily of RPTPs and the implications of proteolysis. Semin Cell Dev Biol 37:108–118
Takahashi H, Craig AM (2013) Protein tyrosine phosphatases PTPdelta, PTPsigma, and LAR: presynaptic hubs for synapse organization. Trends Neurosci 36:522–534
Um JW, Ko J (2013) LAR-RPTPs: synaptic adhesion molecules that shape synapse development. Trends Cell Biol 23:465–475
Johnson KG, Tenney AP, Ghose A, Duckworth AM, Higashi ME, Parfitt K, Marcu O, Heslip TR, Marsh JL, Schwarz TL, Flanagan JG, Van Vactor D (2006) The HSPGs Syndecan and Dallylike bind the receptor phosphatase LAR and exert distinct effects on synaptic development. Neuron 49:517–531
Walzel H, Schulz U, Neels P, Brock J (1999) Galectin-1, a natural ligand for the receptor-type protein tyrosine phosphatase CD45. Immunol Lett 67:193–202
Earl LA, Bi S, Baum LG (2010) N- and O-glycans modulate galectin-1 binding, CD45 signaling, and T cell death. J Biol Chem 285:2232–2244
Clark MC, Pang M, Hsu DK, Liu FT, de Vos S, Gascoyne RD, Said J, Baum LG (2012) Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death. Blood 120:4635–4644
Meng K, Rodriguez-Pena A, Dimitrov T, Chen W, Yamin M, Noda M, Deuel TF (2000) Pleiotrophin signals increased tyrosine phosphorylation of beta beta-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase beta/zeta. Proc Natl Acad Sci U S A 97:2603–2608
Perez-Pinera P, Zhang W, Chang Y, Vega JA, Deuel TF (2007) Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: an alternative mechanism of receptor tyrosine kinase activation. J Biol Chem 282:28683–28690
Marcos T, Ruiz-Martin V, de la Puerta ML, Trinidad AG, Rodriguez Mdel C, de la Fuente MA, Sanchez Crespo M, Alonso A, Bayon Y (2014) Proline-serine-threonine phosphatase interacting protein 1 inhibition of T-cell receptor signaling depends on its SH3 domain. FEBS J 281:3844–3854
Veillette A, Rhee I, Souza CM, Davidson D (2009) PEST family phosphatases in immunity, autoimmunity, and autoinflammatory disorders. Immunol Rev 228:312–324
Guan KL, Broyles SS, Dixon JE (1991) A Tyr/Ser protein phosphatase encoded by vaccinia virus. Nature 350:359–362
Nunes-Xavier C, Roma-Mateo C, Rios P, Tarrega C, Cejudo-Marin R, Tabernero L, Pulido R (2011) Dual-specificity MAP kinase phosphatases as targets of cancer treatment. Anticancer Agents Med Chem 11:109–132
Caunt CJ, Keyse SM (2013) Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J 280:489–504
Hnia K, Vaccari I, Bolino A, Laporte J (2012) Myotubularin phosphoinositide phosphatases: cellular functions and disease pathophysiology. Trends Mol Med 18:317–327
Pulido R, Stoker AW, Hendriks WJ (2013) PTPs emerge as PIPs: protein tyrosine phosphatases with lipid-phosphatase activities in human disease. Hum Mol Genet 22:R66–R76
Alonso A, Burkhalter S, Sasin J, Tautz L, Bogetz J, Huynh H, Bremer MC, Holsinger LJ, Godzik A, Mustelin T (2004) The minimal essential core of a cysteine-based protein-tyrosine phosphatase revealed by a novel 16-kDa VH1-like phosphatase, VHZ. J Biol Chem 279:35768–35774
Todd JL, Tanner KG, Denu JM (1999) Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway. J Biol Chem 274:13271–13280
Alonso A, Saxena M, Williams S, Mustelin T (2001) Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. J Biol Chem 276:4766–4771
Manford A, Xia T, Saxena AK, Stefan C, Hu F, Emr SD, Mao Y (2010) Crystal structure of the yeast Sac1: implications for its phosphoinositide phosphatase function. EMBO J 29:1489–1498
Sasaki T, Takasuga S, Sasaki J, Kofuji S, Eguchi S, Yamazaki M, Suzuki A (2009) Mammalian phosphoinositide kinases and phosphatases. Prog Lipid Res 48:307–343
Hughes WE, Cooke FT, Parker PJ (2000) Sac phosphatase domain proteins. Biochem J 350(Pt 2):337–352
Dyson JM, Fedele CG, Davies EM, Becanovic J, Mitchell CA (2012) Phosphoinositide phosphatases: just as important as the kinases. Subcell Biochem 58:215–279
Hsu F, Mao Y (2015) The structure of phosphoinositide phosphatases: insights into substrate specificity and catalysis. Biochim Biophys Acta 1851:698–710
Huang SM, Hancock MK, Pitman JL, Orth AP, Gekakis N (2009) Negative regulators of insulin signaling revealed in a genome-wide functional screen. PLoS One 4:e6871
Mullaney EJ, Ullah AH (2003) The term phytase comprises several different classes of enzymes. Biochem Biophys Res Commun 312:179–184
Puhl AA, Gruninger RJ, Greiner R, Janzen TW, Mosimann SC, Selinger LB (2007) Kinetic and structural analysis of a bacterial protein tyrosine phosphatase-like myo-inositol polyphosphatase. Protein Sci 16:1368–1378
Huang H, Zhang R, Fu D, Luo J, Li Z, Luo H, Shi P, Yang P, Diao Q, Yao B (2011) Diversity, abundance and characterization of ruminal cysteine phytases suggest their important role in phytate degradation. Environ Microbiol 13:747–757
Chu HM, Guo RT, Lin TW, Chou CC, Shr HL, Lai HL, Tang TY, Cheng KJ, Selinger BL, Wang AH (2004) Structures of Selenomonas ruminantium phytase in complex with persulfated phytate: DSP phytase fold and mechanism for sequential substrate hydrolysis. Structure 12:2015–2024
Adams MS, Gammill LS, Bronner-Fraser M (2008) Discovery of transcription factors and other candidate regulators of neural crest development. Dev Dyn 237:1021–1033
Gammill LS, Bronner-Fraser M (2002) Genomic analysis of neural crest induction. Development 129:5731–5741
Roffers-Agarwal J, Hutt KJ, Gammill LS (2012) Paladin is an antiphosphatase that regulates neural crest cell formation and migration. Dev Biol 371:180–190
Wallgard E, Nitzsche A, Larsson J, Guo X, Dieterich LC, Dimberg A, Olofsson T, Ponten FC, Makinen T, Kalen M, Hellstrom M (2012) Paladin (X99384) is expressed in the vasculature and shifts from endothelial to vascular smooth muscle cells during mouse development. Dev Dyn 241:770–786
Ivetac I, Munday AD, Kisseleva MV, Zhang XM, Luff S, Tiganis T, Whisstock JC, Rowe T, Majerus PW, Mitchell CA (2005) The type Ialpha inositol polyphosphate 4-phosphatase generates and terminates phosphoinositide 3-kinase signals on endosomes and the plasma membrane. Mol Biol Cell 16:2218–2233
Barnache S, Le Scolan E, Kosmider O, Denis N, Moreau-Gachelin F (2006) Phosphati-dylinositol 4-phosphatase type II is an erythropoietin-responsive gene. Oncogene 25:|1420–1423
Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, Barretina J, Lin WM, Rameh L, Salmena L, Pandolfi PP, Cantley LC (2009) Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 16:115–125
Nystuen A, Legare ME, Shultz LD, Frankel WN (2001) A null mutation in inositol polyphosphate 4-phosphatase type I causes selective neuronal loss in weeble mutant mice. Neuron 32:203–212
Sasaki J, Kofuji S, Itoh R, Momiyama T, Takayama K, Murakami H, Chida S, Tsuya Y, Takasuga S, Eguchi S, Asanuma K, Horie Y, Miura K, Davies EM, Mitchell C, Yamazaki M, Hirai H, Takenawa T, Suzuki A, Sasaki T (2010) The PtdIns(3,4)P(2) phosphatase INPP4A is a suppressor of excitotoxic neuronal death. Nature 465:497–501
Sharma M, Batra J, Mabalirajan U, Sharma S, Nagarkatti R, Aich J, Sharma SK, Niphadkar PV, Ghosh B (2008) A genetic variation in inositol polyphosphate 4 phosphatase a enhances susceptibility to asthma. Am J Respir Crit Care Med 177:712–719
Marjanovic J, Wilson MP, Zhang C, Zou J, Nicholas P, Majerus PW (2011) The role of inositol polyphosphate 4-phosphatase 1 in platelet function using a weeble mouse model. Adv Enzyme Regul 51:101–105
Aich J, Mabalirajan U, Ahmad T, Agrawal A, Ghosh B (2012) Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation. Nat Commun 3:877
Agoulnik IU, Hodgson MC, Bowden WA, Ittmann MM (2011) INPP4B: the new kid on the PI3K block. Oncotarget 2:321–328
Hodgson MC, Deryugina EI, Suarez E, Lopez SM, Lin D, Xue H, Gorlov IP, Wang Y, Agoulnik IU (2014) INPP4B suppresses prostate cancer cell invasion. Cell Commun Signal 12:61
Chew CL, Lunardi A, Gulluni F, Ruan DT, Chen M, Salmena LPD, Nishino M, Papa A, Ng C, Fung J, Clohessy JG, Sasaki J, Sasaki T, Bronson RT, Hirsch E, Pandolfi PP (2015) In vivo role of INPP4B in tumor and metastasis suppression through regulation of PI3K/AKT signaling at endosomes. Cancer Discov 5(7):740–751
Kofuji S, Kimura H, Nakanishi H, Nanjo H, Takasuga S, Liu H, Eguchi S, Nakamura R, Itoh R, Ueno N, Asanuma K, Huang M, Koizumi A, Habuchi T, Yamazaki M, Suzuki A, Sasaki J, Sasaki T (2015) INPP4B is a PtdIns(3,4,5)P3 phosphatase that can act as a tumor suppressor. Cancer Discov 5(7):730–739
Ferron M, Boudiffa M, Arsenault M, Rached M, Pata M, Giroux S, Elfassihi L, Kisseleva M, Majerus PW, Rousseau F, Vacher J (2011) Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans. Cell Metab 14:466–477
Ungewickell A, Hugge C, Kisseleva M, Chang SC, Zou J, Feng Y, Galyov EE, Wilson M, Majerus PW (2005) The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases. Proc Natl Acad Sci U S A 102:18854–18859
Zou J, Marjanovic J, Kisseleva MV, Wilson M, Majerus PW (2007) Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis. Proc Natl Acad Sci U S A 104:16834–16839
Xiang K, Nagaike T, Xiang S, Kilic T, Beh MM, Manley JL, Tong L (2010) Crystal structure of the human symplekin-Ssu72-CTD phosphopeptide complex. Nature 467:729–733
Souza AC, Azoubel S, Queiroz KC, Peppelenbosch MP, Ferreira CV (2009) From immune response to cancer: a spot on the low molecular weight protein tyrosine phosphatase. Cell Mol Life Sci 66:1140–1153
Alho I, Costa L, Bicho M, Coelho C (2013) The role of low-molecular-weight protein tyrosine phosphatase (LMW-PTP ACP1) in oncogenesis. Tumour Biol 34:1979–1989
Zegers I, Martins JC, Willem R, Wyns L, Messens J (2001) Arsenate reductase from S. aureus plasmid pI258 is a phosphatase drafted for redox duty. Nat Struct Biol 8:843–847
Bennett MS, Guan Z, Laurberg M, Su XD (2001) Bacillus subtilis arsenate reductase is structurally and functionally similar to low molecular weight protein tyrosine phosphatases. Proc Natl Acad Sci U S A 98:13577–13582
Xiang K, Manley JL, Tong L (2012) An unexpected binding mode for a Pol II CTD peptide phosphorylated at Ser7 in the active site of the CTD phosphatase Ssu72. Genes Dev 26:2265–2270
Krishnamurthy S, He X, Reyes-Reyes M, Moore C, Hampsey M (2004) Ssu72 Is an RNA polymerase II CTD phosphatase. Mol Cell 14:387–394
Zhang DW, Mosley AL, Ramisetty SR, Rodriguez-Molina JB, Washburn MP, Ansari AZ (2012) Ssu72 phosphatase-dependent erasure of phospho-Ser7 marks on the RNA polymerase II C-terminal domain is essential for viability and transcription termination. J Biol Chem 287:8541–8551
Kim HS, Baek KH, Ha GH, Lee JC, Kim YN, Lee J, Park HY, Lee NR, Lee H, Cho Y, Lee CW (2010) The hsSsu72 phosphatase is a cohesin-binding protein that regulates the resolution of sister chromatid arm cohesion. EMBO J 29:3544–3557
Kim HS, Kim SH, Park HY, Lee J, Yoon JH, Choi S, Ryu SH, Lee H, Cho HS, Lee CW (2013) Functional interplay between Aurora B kinase and Ssu72 phosphatase regulates sister chromatid cohesion. Nat Commun 4:2631
Boutros R, Lobjois V, Ducommun B (2007) CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer 7:495–507
Boutros R, Dozier C, Ducommun B (2006) The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol 18:185–191
Reynolds RA, Yem AW, Wolfe CL, Deibel MR Jr, Chidester CG, Watenpaugh KD (1999) Crystal structure of the catalytic subunit of Cdc25B required for G2/M phase transition of the cell cycle. J Mol Biol 293:559–568
Fauman EB, Cogswell JP, Lovejoy B, Rocque WJ, Holmes W, Montana VG, Piwnica-Worms H, Rink MJ, Saper MA (1998) Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A. Cell 93:617–625
Ploegman JH, Drent G, Kalk KH, Hol WG, Heinrikson RL, Keim P, Weng L, Russell J (1978) The covalent and tertiary structure of bovine liver rhodanese. Nature 273:124–129
Bordo D, Bork P (2002) The rhodanese/Cdc25 phosphatase superfamily. Sequence-structure-function relations. EMBO Rep 3:741–746
Tanoue T, Nishida E (2003) Molecular recognitions in the MAP kinase cascades. Cell Signal 15:455–462
Cipollone R, Ascenzi P, Visca P (2007) Common themes and variations in the rhodanese superfamily. IUBMB Life 59:51–59
Rudolph J (2002) Catalytic mechanism of Cdc25. Biochemistry 41:14613–14623
Arantes GM (2008) The catalytic acid in the dephosphorylation of the Cdk2-pTpY/CycA protein complex by Cdc25B phosphatase. J Phys Chem 112:15244–15247
Patterson KI, Brummer T, O’Brien PM, Daly RJ (2009) Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J 418:475–489
Tadjuidje E, Hegde RS (2013) The Eyes Absent proteins in development and disease. Cell Mol Life Sci 70:1897–1913
Xu PX, Woo I, Her H, Beier DR, Maas RL (1997) Mouse Eya homologues of the Drosophila eyes absent gene require Pax6 for expression in lens and nasal placode. Development 124:219–231
Ohto H, Kamada S, Tago K, Tominaga SI, Ozaki H, Sato S, Kawakami K (1999) Cooperation of six and eya in activation of their target genes through nuclear translocation of Eya. Mol Cell Biol 19:6815–6824
Li X, Oghi KA, Zhang J, Krones A, Bush KT, Glass CK, Nigam SK, Aggarwal AK, Maas R, Rose DW, Rosenfeld MG (2003) Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 426:247–254
Rayapureddi JP, Kattamuri C, Steinmetz BD, Frankfort BJ, Ostrin EJ, Mardon G, Hegde RS (2003) Eyes absent represents a class of protein tyrosine phosphatases. Nature 426:295–298
Tootle TL, Silver SJ, Davies EL, Newman V, Latek RR, Mills IA, Selengut JD, Parlikar BE, Rebay I (2003) The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature 426:299–302
Okabe Y, Sano T, Nagata S (2009) Regulation of the innate immune response by threonine-phosphatase of Eyes absent. Nature 460:520–524
Sano T, Nagata S (2011) Characterization of the threonine-phosphatase of mouse eyes absent 3. FEBS Lett 585:2714–2719
Cook PJ, Ju BG, Telese F, Wang X, Glass CK, Rosenfeld MG (2009) Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 458:591–596
Krishnan N, Jeong DG, Jung SK, Ryu SE, Xiao A, Allis CD, Kim SJ, Tonks NK (2009) Dephosphorylation of the C-terminal tyrosyl residue of the DNA damage-related histone H2A.X is mediated by the protein phosphatase eyes absent. J Biol Chem 284(24):16066–16070
Rigden DJ (2008) The histidine phosphatase superfamily: structure and function. Biochem J 409:333–348
Kowanetz K, Crosetto N, Haglund K, Schmidt MH, Heldin CH, Dikic I (2004) Suppressors of T-cell receptor signaling Sts-1 and Sts-2 bind to Cbl and inhibit endocytosis of receptor tyrosine kinases. J Biol Chem 279:32786–32795
Carpino N, Kobayashi R, Zang H, Takahashi Y, Jou ST, Feng J, Nakajima H, Ihle JN (2002) Identification, cDNA cloning, and targeted deletion of p70, a novel, ubiquitously expressed SH3 domain-containing protein. Mol Cell Biol 22:7491–7500
Feshchenko EA, Smirnova EV, Swaminathan G, Teckchandani AM, Agrawal R, Band H, Zhang X, Annan RS, Carr SA, Tsygankov AY (2004) TULA: an SH3- and UBA-containing protein that binds to c-Cbl and ubiquitin. Oncogene 23:4690–4706
Wattenhofer M, Shibuya K, Kudoh J, Lyle R, Michaud J, Rossier C, Kawasaki K, Asakawa S, Minoshima S, Berry A, Bonne-Tamir B, Shimizu N, Antonarakis SE, Scott HS (2001) Isolation and characterization of the UBASH3A gene on 21q22.3 encoding a potential nuclear protein with a novel combination of domains. Hum Genet 108:140–147
Hoeller D, Crosetto N, Blagoev B, Raiborg C, Tikkanen R, Wagner S, Kowanetz K, Breitling R, Mann M, Stenmark H, Dikic I (2006) Regulation of ubiquitin-binding proteins by monoubiquitination. Nat Cell Biol 8:163–169
Carpino N, Turner S, Mekala D, Takahashi Y, Zang H, Geiger TL, Doherty P, Ihle JN (2004) Regulation of ZAP-70 activation and TCR signaling by two related proteins, Sts-1 and Sts-2. Immunity 20:37–46
Mikhailik A, Ford B, Keller J, Chen Y, Nassar N, Carpino N (2007) A phosphatase activity of Sts-1 contributes to the suppression of TCR signaling. Mol Cell 27:486–497
Agrawal R, Carpino N, Tsygankov A (2008) TULA proteins regulate activity of the protein tyrosine kinase Syk. J Cell Biochem 104:953–964
San Luis B, Sondgeroth B, Nassar N, Carpino N (2011) Sts-2 is a phosphatase that negatively regulates zeta-associated protein (ZAP)-70 and T cell receptor signaling pathways. J Biol Chem 286:15943–15954
Thomas DH, Getz TM, Newman TN, Dangelmaier CA, Carpino N, Kunapuli SP, Tsygankov AY, Daniel JL (2010) A novel histidine tyrosine phosphatase, TULA-2, associates with Syk and negatively regulates GPVI signaling in platelets. Blood 116:2570–2578
Chen X, Ren L, Kim S, Carpino N, Daniel JL, Kunapuli SP, Tsygankov AY, Pei D (2010) Determination of the substrate specificity of protein-tyrosine phosphatase TULA-2 and identification of Syk as a TULA-2 substrate. J Biol Chem 285:31268–31276
Raguz J, Wagner S, Dikic I, Hoeller D (2007) Suppressor of T-cell receptor signalling 1 and 2 differentially regulate endocytosis and signalling of receptor tyrosine kinases. FEBS Lett 581:4767–4772
Tsygankov AY (2013) TULA-family proteins: a new class of cellular regulators. J Cell Physiol 228:43–49
Lee ST, Feng M, Wei Y, Li Z, Qiao Y, Guan P, Jiang X, Wong CH, Huynh K, Wang J, Li J, Karuturi KM, Tan EY, Hoon DS, Kang Y, Yu Q (2013) Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis. Proc Natl Acad Sci U S A 110:11121–11126
Veeramani S, Lee MS, Lin MF (2009) Revisiting histidine-dependent acid phosphatases: a distinct group of tyrosine phosphatases. Trends Biochem Sci 34:273–278
Veeramani S, Yuan TC, Chen SJ, Lin FF, Petersen JE, Shaheduzzaman S, Srivastava S, MacDonald RG, Lin MF (2005) Cellular prostatic acid phosphatase: a protein tyrosine phosphatase involved in androgen-independent proliferation of prostate cancer. Endocr Relat Cancer 12:805–822
Chuang TD, Chen SJ, Lin FF, Veeramani S, Kumar S, Batra SK, Tu Y, Lin MF (2010) Human prostatic acid phosphatase, an authentic tyrosine phosphatase, dephosphorylates ErbB-2 and regulates prostate cancer cell growth. J Biol Chem 285:23598–23606
Fleisig H, El-Din El-Husseini A, Vincent SR (2004) Regulation of ErbB4 phosphorylation and cleavage by a novel histidine acid phosphatase. Neuroscience 127:91–100
Muniyan S, Ingersoll MA, Batra SK, Lin MF (2014) Cellular prostatic acid phosphatase, a PTEN-functional homologue in prostate epithelia, functions as a prostate-specific tumor suppressor. Biochim Biophys Acta 1846:88–98
Quintero IB, Herrala AM, Araujo CL, Pulkka AE, Hautaniemi S, Ovaska K, Pryazhnikov E, Kulesskiy E, Ruuth MK, Soini Y, Sormunen RT, Khirug L, Vihko PT (2013) Transmembrane prostatic acid phosphatase (TMPAP) interacts with snapin and deficient mice develop prostate adenocarcinoma. PLoS One 8:e73072
Seifried A, Schultz J, Gohla A (2013) Human HAD phosphatases: structure, mechanism, and roles in health and disease. FEBS J 280:549–571
Allen KN, Dunaway-Mariano D (2009) Markers of fitness in a successful enzyme superfamily. Curr Opin Struct Biol 19:658–665
Chen Y, Jakoncic J, Carpino N, Nassar N (2009) Structural and functional characterization of the 2H-phosphatase domain of Sts-2 reveals an acid-dependent phosphatase activity. Biochemistry 48:1681–1690
Cousin W, Courseaux A, Ladoux A, Dani C, Peraldi P (2004) Cloning of hOST-PTP: the only example of a protein-tyrosine-phosphatase the function of which has been lost between rodent and human. Biochem Biophys Res Commun 321:259–265
Tapparel C, Reymond A, Girardet C, Guillou L, Lyle R, Lamon C, Hutter P, Antonarakis SE (2003) The TPTE gene family: cellular expression, subcellular localization and alternative splicing. Gene 323:189–199
van Eekelen M, Overvoorde J, van Rooijen C, den Hertog J (2010) Identification and expression of the family of classical protein-tyrosine phosphatases in zebrafish. PLoS One 5:e12573
Hatzihristidis T, Desai N, Hutchins AP, Meng TC, Tremblay ML, Miranda-Saavedra D (2015) A Drosophila-centric view of protein tyrosine phosphatases. FEBS Lett 589:951–966
Morrison DK, Murakami MS, Cleghon V (2000) Protein kinases and phosphatases in the Drosophila genome. J Cell Biol 150:F57–F62
Martin H, Flandez M, Nombela C, Molina M (2005) Protein phosphatases in MAPK signalling: we keep learning from yeast. Mol Microbiol 58:6–16
Roma-Mateo C, Sacristan-Reviriego A, Beresford NJ, Caparros-Martin JA, Culianez-Macia FA, Martin H, Molina M, Tabernero L, Pulido R (2011) Phylogenetic and genetic linkage between novel atypical dual-specificity phosphatases from non-metazoan organisms. Mol Genet Genomics 285:341–354
Hsu F, Mao Y (2013) The Sac domain-containing phosphoinositide phosphatases: structure, function, and disease. Front Biol (Beijing) 8:395–407
Duan G, Li X, Kohn M (2015) The human DEPhOsphorylation database DEPOD: a 2015 update. Nucleic Acids Res 43:D531–D535
Pons T, Paramonov I, Boullosa C, Ibanez K, Rojas AM, Valencia A (2014) A common structural scaffold in CTD phosphatases that supports distinct catalytic mechanisms. Proteins 82:103–118
Heneberg P (2009) Use of protein tyrosine phosphatase inhibitors as promising targeted therapeutic drugs. Curr Med Chem 16:706–733
Heneberg P (2012) Finding the smoking gun: protein tyrosine phosphatases as tools and targets of unicellular microorganisms and viruses. Curr Med Chem 19:1530–1566
Bohmer F, Szedlacsek S, Tabernero L, Ostman A, den Hertog J (2013) Protein tyrosine phosphatase structure-function relationships in regulation and pathogenesis. FEBS J 280:413–431
Ostman A, Hellberg C, Bohmer FD (2006) Protein-tyrosine phosphatases and cancer. Nat Rev Cancer 6:307–320
Tonks NK (2006) Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev 7:833–846
Keyse SM (2008) Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev 27:253–261
Pulido R, Hooft van Huijsduijnen R (2008) Protein tyrosine phosphatases: dual-specificity phosphatases in health and disease. FEBS J 275:848–866
Vang T, Miletic AV, Arimura Y, Tautz L, Rickert RC, Mustelin T (2008) Protein tyrosine phosphatases in autoimmunity. Annu Rev Immunol 26:29–55
Hardy S, Julien SG, Tremblay ML (2012) Impact of oncogenic protein tyrosine phosphatases in cancer. Anticancer Agents Med Chem 12:4–18
Julien SG, Dube N, Hardy S, Tremblay ML (2011) Inside the human cancer tyrosine phosphatome. Nat Rev Cancer 11:35–49
Rhee I, Veillette A (2012) Protein tyrosine phosphatases in lymphocyte activation and autoimmunity. Nat Immunol 13:439–447
Hendriks WJ, Elson A, Harroch S, Pulido R, Stoker A, den Hertog J (2013) Protein tyrosine phosphatases in health and disease. FEBS J 280:708–730
Nunes-Xavier CE, Martin-Perez J, Elson A, Pulido R (2013) Protein tyrosine phosphatases as novel targets in breast cancer therapy. Biochim Biophys Acta 1836:211–226
Tsou RC, Bence KK (2012) Central regulation of metabolism by protein tyrosine phosphatases. Front Neurosci 6:192
Knobler H, Elson A (2014) Metabolic regulation by protein tyrosine phosphatases. J Biomed Res 28:157–168
Rios P, Nunes-Xavier CE, Tabernero L, Kohn M, Pulido R (2014) Dual-specificity phosphatases as molecular targets for inhibition in human disease. Antioxid Redox Signal 20:2251–2273
Stebbing J, Lit LC, Zhang H, Darrington RS, Melaiu O, Rudraraju B, Giamas G (2014) The regulatory roles of phosphatases in cancer. Oncogene 33:939–953
Zhao S, Sedwick D, Wang Z (2015) Genetic alterations of protein tyrosine phosphatases in human cancers. Oncogene 34(30):3885–3894
Lee H, Yi JS, Lawan A, Min K, Bennett AM (2015) Mining the function of protein tyrosine phosphatases in health and disease. Semin Cell Dev Biol 37:66–72
Leslie NR (2012) PTEN: an intercellular peacekeeper? Sci Signal 5:pe50
Boosani CS, Agrawal DK (2013) PTEN modulators: a patent review. Expert Opin Ther Pat 23:569–580
Papa A, Chen M, Pandolfi PP (2013) Pills of PTEN? In and out for tumor suppression. Cell Res 23:1155–1156
Pulido R (2015) PTEN: a yin-yang master regulator protein in health and disease. Methods (San Diego, Calif) 77–78:3–10
Acknowledgements
The work in RP laboratory is supported in part by grants SAF2013-48812-R from Ministerio de Economía y Competitividad (Spain), 2013111011 from Gobierno Vasco, Departamento de Salud (Basque Country, Spain), and BIO13/CI/001/BC from BIOEF/EITB maratoia (Basque Country, Spain).
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Alonso, A., Nunes-Xavier, C.E., Bayón, Y., Pulido, R. (2016). The Extended Family of Protein Tyrosine Phosphatases. In: Pulido, R. (eds) Protein Tyrosine Phosphatases. Methods in Molecular Biology, vol 1447. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3746-2_1
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