Protein tyrosine phosphatases (PTPs) and related enzymes (more than a hundred coded by the human genome) are more numerous than serine/threonine phosphatases. They belong to four families, three of which possess a conserved cysteine for catalysis and some conserved features of 3-dimensional structure. The catalytic mechanism of these PTPs involves the transient formation of a covalently phosphorylated enzyme.

Class 1 cysteine-based PTPs include "classical" PTPs and dual specificity phosphatases (i.e. able to dephosphorylate serine or threonine residues, as well as tyrosines). The "classical" PTPs are further subdivided into receptor-like PTPs (RPTP), which possess a single transmembrane domain and a large extracellular domain, and non-receptor PTPs (NRTPs) which lack such domains. Although the structural features of RPTPs suggest that they may function as receptors, their putative regulatory ligands remain to be identified. RPTPs are involved in cell-cell or cell-matrix interactions and have properties in common with adhesion molecules. Thus, the main role of the extracellular receptor-like domain may be to enrich tyrosine phosphatases at specific locations. RPTPs are implicated, among other functions, in neurite outgrowth, and focal adhesions and adherens junctions regulation.

Many non-receptor PTPs have targeting domains, including SH2 (Src-homology 2), FERM (four-point-one, ezrin, radixin, moesin), and membrane targeting domains. In lymphocytes, for example, SH2-containing PTPs are recruited to specific tyrosine phosphorylated motifs (ITIMs - immunoreceptor tyrosine-based inhibition motifs) and participate in the modulation of the immune response. PTP1B is targeted by its hydrophobic C-terminus to the cytoplasmic face of endoplasmic reticulum membranes.

Dual specificity phosphatases are related to the product of the vaccinia virus H1 gene (VH1). Members of this group, termed MAP-kinases phosphatases (MKPs), dephosphorylate MAP kinases. Several MKPs are induced by MAP kinase pathways and provide a negative feedback mechanism. VH1 gene family also includes enzymes (PTENs and myotubularins) that have a specificity for other substrates such as phosphatidyl-inositol-3-phosphate.

Class II cysteine-based PTPs include a single member in the human genome, the "low molecular weight PTP". Although this enzyme can dephosphorylate a number of tyrosine kinases and their substrates, its precise physiological role is still poorly understood.

Class III cysteine-based PTPs include the three Cdc25 cell cycle regulators. These enzymes are structurally related to a group of sulfurtransferases termed the rhodaneses. Cdc25 plays a critical role in the control of the cell cycle by dephosphorylating the dually phosphorylated N-terminal Thr-Tyr motif of cyclin-dependent kinases (Cdks).

The last and distinct class IV of potential PTPs, characterized by an aspartate-based, cation-dependent catalysis, comprises the EyA gene products. The physiological role of these enzymes in the control of tyrosine phosphorylation is not yet known.

While many phosphatases inhibit the activities of phosphorylation cascades, some activate them. CD45, for example, activates Src family tyrosine kinases by dephosphorylating an inhibitory phosphotyrosine residue, while Cdc25 activates Cdks. In addition to their physiological role, PTPs are used as weapons by pathogenic microorganisms. For instance, one of the virulence genes of Yersinia bacteria (to which belongs the agent of bubonic plague) codes for a PTP.

The specific activities of PTPs are very high and these enzymes are tightly regulated within cells. Mechanisms of control include protein-protein interactions and restriction to specific locations by precise targeting. Reactive oxygen species reversibly inactivate the catalytic cysteine of PTPs and their role in the physiological regulation of PTPs is supported by several studies. Most of the pharmacological inhibitors of PTPs are nonspecific and include agents that mimic phosphorylated residues or oxidize the catalytic cysteine. Since PTP1B opposes insulin action and Cdc25 controls cell cycle, research for specific inhibitors of these enzymes is very active. Some interesting compounds have been identified, including benzofuran/benzothiophene biphenyl oxo-acetic acids and sulfonyl-salicylic acids derivatives as inhibitors of PTP1B.

The Tables below contain accepted modulators and additional information. For a list of additional products, see the "Similar Procucts" section below.

Table 1.Accepted Modulators and Additional Information - Class I cysteine-based PTPs
Table 2.Accepted Modulators and Additional Information - Class II Cys-based and Class III Cys-based

Abbreviations

BpV(phen): Bisperoxo(1,10-phenanthroline)oxovanadate (V)
Cdk: Cyclin-dependent kinase
PTP: Protein tyrosine phosphatase
VH-1: Product of vaccinia virus gene H1

Similar Procucts
Loading

References

1.
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(6):699-711. http://dx.doi.org/10.1016/j.cell.2004.05.018
2.
Andersen JN, Jansen PG, Echwald SM, Mortensen OH, Fukada T, Del Vecchio R, Tonks NK, M?ller NPH. 2004. A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB j.. 18(1):8-30. http://dx.doi.org/10.1096/fj.02-1212rev
3.
Andersen JN, Mortensen OH, Peters GH, Drake PG, Iversen LF, Olsen OH, Jansen PG, Andersen HS, Tonks NK, Møller NPH. 2001. Structural and Evolutionary Relationships among Protein Tyrosine Phosphatase Domains. Mol. Cell. Biol.. 21(21):7117-7136. http://dx.doi.org/10.1128/mcb.21.21.7117-7136.2001
4.
Bahta M, Burke T. 2012. Yersinia pestis and Approaches to Targeting its Outer Protein H Protein-Tyrosine Phosphatase (YopH). CMC. 19(33):5726-5734. http://dx.doi.org/10.2174/092986712803988866
5.
Barr AJ. 2010. Protein tyrosine phosphatases as drug targets: strategies and challenges of inhibitor development. Future Medicinal Chemistry. 2(10):1563-1576. http://dx.doi.org/10.4155/fmc.10.241
6.
Bhattacharyya S, Tracey AS. 2001. Vanadium(V) complexes in enzyme systems: aqueous chemistry, inhibition and molecular modeling in inhibitor design. Journal of Inorganic Biochemistry. 85(1):9-13. http://dx.doi.org/10.1016/s0162-0134(00)00229-4
7.
Bordo D, Bork P. 2002. The rhodanese/Cdc25 phosphatase superfamily. EMBO Rep. 3(8):741-746. http://dx.doi.org/10.1093/embo-reports/kvf150
8.
Chien PN, Ryu SE. 2013. Protein Tyrosine Phosphatase ? in Proteoglycan-Mediated Neural Regeneration Regulation. Mol Neurobiol. 47(1):220-227. http://dx.doi.org/10.1007/s12035-012-8346-x
9.
Farooq A, Zhou M. 2004. Structure and regulation of MAPK phosphatases. Cellular Signalling. 16(7):769-779. http://dx.doi.org/10.1016/j.cellsig.2003.12.008
10.
Goebel-Goody SM, Baum M, Paspalas CD, Fernandez SM, Carty NC, Kurup P, Lombroso PJ. 2012. Therapeutic Implications for Striatal-Enriched Protein Tyrosine Phosphatase (STEP) in Neuropsychiatric Disorders. Pharmacol Rev. 64(1):65-87. http://dx.doi.org/10.1124/pr.110.003053
11.
Keyse SM. 2000. Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Current Opinion in Cell Biology. 12(2):186-192. http://dx.doi.org/10.1016/s0955-0674(99)00075-7
12.
Neel BG, Gu H, Pao L. 2003. The ?Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends in Biochemical Sciences. 28(6):284-293. http://dx.doi.org/10.1016/s0968-0004(03)00091-4
13.
Rhee I, Veillette A. 2012. Protein tyrosine phosphatases in lymphocyte activation and autoimmunity. Nat Immunol. 13(5):439-447. http://dx.doi.org/10.1038/ni.2246
14.
Tonks NK. 2003. PTP1B: From the sidelines to the front lines!. 546(1):140-148. http://dx.doi.org/10.1016/s0014-5793(03)00603-3
15.
Umezawa K, Kawakami M, Watanabe T. 2003. Molecular design and biological activities of protein-tyrosine phosphatase inhibitors. Pharmacology & Therapeutics. 99(1):15-24. http://dx.doi.org/10.1016/s0163-7258(03)00050-0
16.
Unkeless JC, Jin J. 1997. Inhibitory receptors, ITIM sequences and phosphatases. Current Opinion in Immunology. 9(3):338-343. http://dx.doi.org/10.1016/s0952-7915(97)80079-9
17.
Zhang Z. 2002. PROTEINTYROSINEPHOSPHATASES: Structure and Function, Substrate Specificity, and Inhibitor Development. Annu. Rev. Pharmacol. Toxicol.. 42(1):209-234. http://dx.doi.org/10.1146/annurev.pharmtox.42.083001.144616