Protein-tyrosine phosphatases (PTPs) constitute a structurally diverse family of tightly regulated enzymes that are characterized by a conserved catalytic domain with an oxidation-sensitive active-site cysteine residue.
Different PTPs function as negative or positive mediators of signalling triggered by receptor-tyrosine kinases, integrins and cell-adhesion molecules.
The tumour-suppressive function of PTPs is indicated by frequent inactivating mutations of PTPs in colon cancer, and the identification of Ptprj as the gene that confers colon cancer susceptibility in STS/A mice. Also, inactivation of the genes that encode SHP1 and glomerular epithelial protein 1 (GLEPP1) by methylation has been described in haematological malignancies and solid tumours, respectively.
The oncogenic activity of a PTP is best characterized for the mutational activation of SHP2, which occurs in hereditary and sporadic leukaemias and, less frequently, in solid tumours.
Despite technical challenges, recent advances in the design of PTP inhibitors are encouraging with respect to the possibilities of developing novel cancer drugs that function by inhibiting oncogenic PTPs.
Other aspects of PTP biology that might be relevant to cancer research in the future are the regulation of PTPs by oxidation and the putative role of PTPs in angiogenesis.
Tyrosine phosphorylation is an important signalling mechanism in eukaryotic cells. In cancer, oncogenic activation of tyrosine kinases is a common feature, and novel anticancer drugs have been introduced that target these enzymes. Tyrosine phosphorylation is also controlled by protein-tyrosine phosphatases (PTPs). Recent evidence has shown that PTPs can function as tumour suppressors. In addition, some PTPs, including SHP2, positively regulate the signalling of growth-factor receptors, and can be oncogenic. An improved understanding of how these enzymes function and how they are regulated might aid the development of new anticancer agents.
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Blume-Jensen, P. & Hunter, T. Oncogenic kinase signalling. Nature 411, 355–365 (2001).
Sawyers, C. Targeted cancer therapy. Nature 432, 294–297 (2004).
Tonks, N. K., Diltz, C. D. & Fischer, E. H. Purification of the major protein-tyrosine-phosphatases of human placenta. J. Biol. Chem. 263, 6722–6730 (1988).
Andersen, J. N. et al. Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol. Cell. Biol. 21, 7117–7136 (2001). Comprehensive review of the structural similarities and differences of PTPs, coupled with insightful discussions of functional significances.
Östman, A. & Böhmer, F. D. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol. 11, 258–266 (2001).
Alonso, A. et al. Protein tyrosine phosphatases in the human genome. Cell 117, 699–711 (2004).
Ducruet, A. P., Vogt, A., Wipf, P. & Lazo, J. S. Dual specificity protein phosphatases: therapeutic targets for cancer and Alzheimer's disease. Annu. Rev. Pharmacol. Toxicol. 45, 725–750 (2005).
Raugei, G., Ramponi, G. & Chiarugi, P. Low molecular weight protein tyrosine phosphatases: small, but smart. Cell. Mol. Life Sci. 59, 941–949 (2002).
Sulis, M. L. & Parsons, R. PTEN: from pathology to biology. Trends Cell Biol. 13, 478–483 (2003).
Mauro, L. J. & Dixon, J. E. 'Zip codes' direct intracellular protein tyrosine phosphatases to the correct cellular 'address'. Trends Biochem. Sci. 19, 151–155 (1994).
Zhang, Z. Y. et al. Substrate specificity of the protein tyrosine phosphatases. Proc. Natl Acad. Sci. USA 90, 4446–4450 (1993).
Flint, A. J., Tiganis, T., Barford, D. & Tonks, N. K. Development of “substrate-trapping” mutants to identify physiological substrates of protein tyrosine phosphatases. Proc. Natl Acad. Sci. USA 94, 1680–1685 (1997).
Kovalenko, M. et al. Site-selective dephosphorylation of the platelet-derived growth factor β-receptor by the receptor-like protein-tyrosine phosphatase DEP-1. J. Biol. Chem. 275, 16219–16226 (2000).
Persson, C. et al. Site-selective regulation of platelet-derived growth factor β receptor tyrosine phosphorylation by T-cell protein tyrosine phosphatase. Mol. Cell. Biol. 24, 2190–201 (2004).
Jia, Z., Barford, D., Flint, A. J. & Tonks, N. K. Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B. Science 268, 1754–1758 (1995). The first example of PTP co-crystalized with substrate, providing insights into catalysis and determinants of substrate specificity.
Salmeen, A., Andersen, J. N., Myers, M. P., Tonks, N. K. & Barford, D. Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Mol. Cell 6, 1401–1412 (2000).
Haj, F. G., Verveer, P. J., Squire, A., Neel, B. G. & Bastiaens, P. I. Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science 295, 1708–1711 (2002). Technically elegant study demonstrating that interactions between PTPs and their substrate occur in a spatially restricted manner.
Frangioni, J. V., Oda, A., Smith, M., Salzman, E. W. & Neel, B. G. Calpain-catalyzed cleavage and subcellular relocation of protein phosphotyrosine phosphatase 1B (PTP-1B) in human platelets. EMBO J. 12, 4843–4856 (1993).
Gulati, P., Markova, B., Göttlicher, M., Böhmer, F. D. & Herrlich, P. A. UVA inactivates protein tyrosine phosphatases by calpain-mediated degradation. EMBO Rep. 5, 812–817 (2004).
Desai, D. M., Sap, J., Schlessinger, J. & Weiss, A. Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase. Cell 73, 541–554 (1993).
Majeti, R., Bilwes, A. M., Noel, J. P., Hunter, T. & Weiss, A. Dimerization-induced inhibition of receptor protein tyrosine phosphatase function through an inhibitory wedge. Science 279, 88–91 (1998).
Bilwes, A. M., den Hertog, J., Hunter, T. & Noel, J. P. Structural basis for inhibition of receptor protein-tyrosine phosphatase-α by dimerization. Nature 382, 555–559 (1996).
Jiang, G. et al. Dimerization inhibits the activity of receptor-like protein-tyrosine phosphatase-α. Nature 401, 606–610 (1999).
Nam, H. J., Poy, F., Krueger, N. X., Saito, H. & Frederick, C. A. Crystal structure of the tandem phosphatase domains of RPTP LAR. Cell 97, 449–457 (1999).
Nam, H. J., Poy, F., Saito, H. & Frederick, C. A. Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45. J. Exp. Med. 201, 441–452 (2005).
Brady-Kalnay, S. M., Rimm, D. L. & Tonks, N. K. Receptor protein tyrosine phosphatase PTPm associates with cadherins and catenins in vivo. J. Cell. Biol. 130, 977–986 (1995).
Sap, J., Jiang, Y. P., Friedlander, D., Grumet, M. & Schlessinger, J. Receptor tyrosine phosphatase R-PTP-κ mediates homophilic binding. Mol. Cell. Biol. 14, 1–9 (1994).
Sörby, M., Sandström, J. & Östman, A. An extracellular ligand increases the specific activity of the receptor-like protein tyrosine phosphatase DEP-1. Oncogene 20, 5219–5224 (2001).
Meng, K. et al. Pleiotrophin signals increased tyrosine phosphorylation of β-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase β/ζ. Proc. Natl Acad. Sci. USA 97, 2603–2608 (2000).
Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).
Haj, F. G., Markova, B., Klaman, L. D., Böhmer, F. D. & Neel, B. G. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B. J. Biol. Chem. 278, 739–744 (2003).
Neel, B. G., Gu, H. & Pao, L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284–293 (2003).
Guo, W. & Giancotti, F. G. Integrin signalling during tumour progression. Nature Rev. Mol. Cell Biol. 5, 816–826 (2004).
Cavallaro, U. & Christofori, G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nature Rev. Cancer 4, 118–132 (2004).
Lilien, J. & Balsamo, J. The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of β-catenin. Curr. Opin. Cell Biol. 17, 459–465 (2005).
Sui, X. F. et al. Receptor protein tyrosine phosphatase μ regulates the paracellular pathway in human lung microvascular endothelia. Am. J. Pathol. 166, 1247–1258 (2005).
Kappert, K., Peters, K. G., Böhmer, F. D. & Östman, A. Tyrosine phosphatases in vessel wall signaling. Cardiovasc. Res. 65, 587–598 (2005).
Larsen, M., Tremblay, M. L. & Yamada, K. M. Phosphatases in cell-matrix adhesion and migration. Nature Rev. Mol. Cell Biol. 4, 700–711 (2003).
Brown-Shimer, S., Johnson, K. A., Hill, D. E. & Bruskin, A. M. Effect of protein tyrosine phosphatase 1B expression on transformation by the human neu oncogene. Cancer Res. 52, 478–482 (1992).
Bardelli, A. et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300, 949 (2003).
Stephens, P. et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431, 525–526 (2004).
Wang, Z. et al. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304, 1164–1166 (2004). A systematic and ambitious study demonstrating that inactivation of PTP is a frequent event in a common human tumour type.
Aricescu, A. R. et al. Molecular analysis of receptor protein tyrosine phosphatase μ mediated cell adhesion. EMBO J. 45, 701–712 (2006).
Keane, M. M., Lowrey, G. A., Ettenberg, S. A., Dayton, M. A. & Lipkowitz, S. The protein tyrosine phosphatase DEP-1 is induced during differentiation and inhibits growth of breast cancer cells. Cancer Res. 56, 4236–4243 (1996).
Trapasso, F. et al. Rat protein tyrosine phosphatase eta suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27Kip1. Mol. Cell. Biol. 20, 9236–9246 (2000).
Iuliano, R. et al. An adenovirus carrying the rat protein tyrosine phosphatase e suppresses the growth of human thyroid carcinoma cell lines in vitro and in vivo. Cancer Res. 63, 882–886 (2003).
Trapasso, F. et al. Restoration of receptor-type protein tyrosine phosphatase ε function inhibits human pancreatic carcinoma cell growth in vitro and in vivo. Carcinogenesis 25, 2107–2114 (2004).
Ruivenkamp, C. A. et al. Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nature Genet. 31, 295–300 (2002). A study that combines mouse genetics and analyses of human tumor samples and provides strong evidence for the tumour-suppressive functions of DEP1.
Moen, C. J., Groot, P. C., Hart, A. A., Snoek, M. & Demant, P. Fine mapping of colon tumor susceptibility (Scc) genes in the mouse, different from the genes known to be somatically mutated in colon cancer. Proc. Natl Acad. Sci. USA 93, 1082–1086 (1996).
Ruivenkamp, C. et al. LOH of PTPRJ occurs early in colorectal cancer and is associated with chromosomal loss of 18q12–21. Oncogene 22, 3472–3474 (2003).
Iuliano, R. et al. The tyrosine phosphatase PTPRJ/DEP-1 genotype affects thyroid carcinogenesis. Oncogene 23, 8432–8438 (2004).
van Puijenbroek, M. et al. Mass spectrometry-based loss of heterozygosity analysis of single-nucleotide polymorphism loci in paraffin embedded tumors using the MassEXTEND assay: single-nucleotide polymorphism loss of heterozygosity analysis of the protein tyrosine phosphatase receptor type J in familial colorectal cancer. J. Mol. Diagn. 7, 623–630 (2005).
Lesueur, F. et al. Allelic association of the human homologue of the mouse modifier Ptprj with breast cancer. Hum. Mol. Genet. 14, 2349–2356 (2005).
Palka, H. L., Park, M. & Tonks, N. K. Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase DEP-1. J. Biol. Chem. 278, 5728–5735 (2003).
Jandt, E., Denner, K., Kovalenko, M., Östman, A. & Böhmer, F. D. The protein-tyrosine phosphatase DEP-1 modulates growth factor-stimulated cell migration and cell–matrix adhesion. Oncogene 22, 4175–4185 (2003).
Grazia Lampugnani, M. et al. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, β-catenin, and the phosphatase DEP-1/CD148. J. Cell Biol. 161, 793–804 (2003).
Berset, T. A., Hoier, E. F. & Hajnal, A. The C. elegans homolog of the mammalian tumor suppressor Dep-1/Scc1 inhibits EGFR signaling to regulate binary cell fate decisions. Genes Dev. 19, 1328–1340 (2005).
Le Pera, I. et al. The rat tyrosine phosphatase e increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue. Oncogene 24, 3187–3195 (2005).
Holsinger, L. J., Ward, K., Duffield, B., Zachwieja, J. & Jallal, B. The transmembrane receptor protein tyrosine phosphatase DEP1 interacts with p120(ctn). Oncogene 21, 7067–7076 (2002).
MacKeigan, J. P., Murphy, L. O. & Blenis, J. Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nature Cell Biol. 7, 591–600 (2005).
Takahashi, T. et al. A mutant receptor tyrosine phosphatase, CD148, causes defects in vascular development. Mol. Cell. Biol. 23, 1817–1831 (2003).
Feinberg, A. P. & Tycko, B. The history of cancer epigenetics. Nature Rev. Cancer 4, 143–153 (2004).
Zhang, Q., Raghunath, P. N., Vonderheid, E., Odum, N. & Wasik, M. A. Lack of phosphotyrosine phosphatase SHP-1 expression in malignant T-cell lymphoma cells results from methylation of the SHP-1 promoter. Am. J. Pathol. 157, 1137–1146 (2000). A study that identifies promoter methylation as a mechanism for PTP inactivation.
Khoury, J. D., Rassidakis, G. Z., Medeiros, L. J., Amin, H. M. & Lai, R. Methylation of SHP1 gene and loss of SHP1 protein expression are frequent in systemic anaplastic large cell lymphoma. Blood 104, 1580–1581 (2004).
Oka, T. et al. Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res. 62, 6390–6394 (2002).
Chim, C. S., Fung, T. K., Cheung, W. C., Liang, R. & Kwong, Y. L. SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak–STAT pathway. Blood 103, 4630–4635 (2004).
Zhang, Q. et al. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc. Natl Acad. Sci. USA 102, 6948–6953 (2005).
Motiwala, T. et al. Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas. Oncogene 22, 6319–6331 (2003).
Motiwala, T. et al. Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer. Proc. Natl Acad. Sci. USA 101, 13844–13849 (2004).
Wharram, B. L. et al. Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate. J. Clin. Invest. 106, 1281–1290 (2000).
Feng, G. S. Shp-2 tyrosine phosphatase: signaling one cell or many. Exp. Cell. Res. 253, 47–54 (1999).
Zhan, Y. & O'Rourke, D. M. SHP-2-dependent mitogen-activated protein kinase activation regulates EGFRvIII but not wild-type epidermal growth factor receptor phosphorylation and glioblastoma cell survival. Cancer Res. 64, 8292–8298 (2004).
D'Alessio, A. et al. The tyrosine phosphatase Shp-2 mediates intracellular signaling initiated by Ret mutants. Endocrinology 144, 4298–4305 (2003).
Agazie, Y. M., Movilla, N., Ischenko, I. & Hayman, M. J. The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3. Oncogene 22, 6909–6918 (2003).
Bentires-Alj, M. et al. A role for the scaffolding adapter GAB2 in breast cancer. Nature Med. 12, 114–121 (2006).
Sattler, M. et al. Critical role for Gab2 in transformation by BCR–ABL. Cancer Cell 1, 479–492 (2002).
Hatakeyama, M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nature Rev. Cancer 4, 688–694 (2004).
Klinghoffer, R. A. & Kazlauskas, A. Identification of a putative Syp substrate, the PDGFβ receptor. J. Biol. Chem. 270, 22208–22217 (1995). Analysis of PDGFR dephosphorylation by SHP2 in vitro showed a preferred dephoshorylation of the binding site for RASGAP. The authors propose that this might be the underlying mechanism for the positive regulation of Ras signalling by SHP2, a finding that was later extended by others to further RTKs.
Montagner, A. et al. A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. J. Biol. Chem. 280, 5350–5360 (2005).
Zhang, S. Q. et al. Shp2 regulates SRC family kinase activity and Ras–Erk activation by controlling Csk recruitment. Mol. Cell 13, 341–355 (2004).
Ren, Y. et al. Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor. J. Biol. Chem. 279, 8497–8505 (2004).
Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A. & Bennett, A. M. The major vault protein is a novel substrate for the tyrosine phosphatase SHP-2 and scaffold protein in epidermal growth factor signaling. J. Biol. Chem. 279, 29374–29385 (2004).
Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genet. 29, 465–468 (2001). The discovery that missense mutations in PTPN11 cause Noonan syndrome, which is an autosomal-dominant disorder, in about 50% of patients. The position of amino-acid exchanges and modelling studies led the authors to suggest that these mutations might cause activation of SHP2.
Tartaglia, M. & Gelb, B. D. Germ-line and somatic PTPN11 mutations in human disease. Eur. J. Med. Genet. 48, 81–96 (2005).
Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genet. 34, 148–150 (2003).
Loh, M. L. et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103, 2325–2331 (2004).
Tartaglia, M. et al. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood 104, 307–313 (2004).
Bentires-Alj, M. et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 64, 8816–8820 (2004).
Tartaglia, M. et al. Somatic PTPN11 mutations in childhood acute myeloid leukaemia. Br. J. Haematol. 129, 333–339 (2005).
Hof, P., Pluskey, S., Dhe-Paganon, S., Eck, M. J. & Shoelson, S. E. Crystal structure of the tyrosine phosphatase SHP-2. Cell 92, 441–450 (1998).
O'Reilly, A. M., Pluskey, S., Shoelson, S. E. & Neel, B. G. Activated mutants of SHP-2 preferentially induce elongation of Xenopus animal caps. Mol. Cell. Biol. 20, 299–311 (2000).
Keilhack, H., David, F. S., McGregor, M., Cantley, L. C. & Neel, B. G. Diverse biochemical properties of Shp2 mutants: implications for disease phenotypes. J. Biol. Chem. 280, 30984–30993 (2005). A thorough biochemical analysis of different disease-associated SHP2 mutants showed unexpected properties, such as altered susceptibility to phosphopeptide ligand activation, and altered substrate selectivity.
Mohi, M. G. et al. Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell 7, 179–191 (2005). A disease model using retroviral transduction of primary mouse bone marrow allowed to characterize different leukaemia-associated SHP2 variants and the role of different protein domains of SHP2 for leukaemogenesis.
Schubbert, S. et al. Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Blood 106, 311–317 (2005).
Araki, T. et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nature Med. 10, 849–857 (2004).
Niihori, T. et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J. Hum. Genet. 50, 192–202 (2005).
Chan, R. J. et al. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 105, 3737–3742 (2005).
Ponniah, S., Wang, D. Z., Lim, K. L. & Pallen, C. J. Targeted disruption of the tyrosine phosphatase PTPα leads to constitutive downregulation of the kinases Src and Fyn. Curr. Biol. 9, 535–538 (1999).
Su, J., Muranjan, M. & Sap, J. Receptor protein tyrosine phosphatase α activates Src-family kinases and controls integrin-mediated responses in fibroblasts. Curr. Biol. 9, 505–511 (1999).
Zheng, X. M., Wang, Y. & Pallen, C. J. Cell transformation and activation of pp60c-src by overexpression of a protein tyrosine phosphatase. Nature 359, 336–339 (1992).
Tabiti, K., Smith, D. R., Goh, H. S. & Pallen, C. J. Increased mRNA expression of the receptor-like protein tyrosine phosphatase α in late stage colon carcinomas. Cancer Lett. 93, 239–248 (1995).
Ardini, E. et al. Expression of protein tyrosine phosphatase α (RPTPα) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo. Oncogene 19, 4979–4987 (2000).
Elson, A. Protein tyrosine phosphatase epsilon increases the risk of mammary hyperplasia and mammary tumors in transgenic mice. Oncogene 18, 7535–7542 (1999).
Gil-Henn, H. & Elson, A. Tyrosine phosphatase-epsilon activates Src and supports the transformed phenotype of Neu-induced mammary tumor cells. J. Biol. Chem. 278, 15579–15586 (2003).
Kroll, J. & Waltenberger, J. The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J. Biol. Chem. 272, 32521–32527 (1997).
Seo, D. W. et al. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114, 171–180 (2003).
Guo, D. Q. et al. Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation. J. Biol. Chem. 275, 11216–11221 (2000).
Fachinger, G., Deutsch, U. & Risau, W. Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the angiopoietin receptor Tie-2. Oncogene 18, 5948–53 (1999).
Lambeng, N. et al. Vascular endothelial-cadherin tyrosine phosphorylation in angiogenic and quiescent adult tissues. Circ. Res. 96, 384–391 (2005).
Waltenberger, J., Mayr, U., Pentz, S. & Hombach, V. Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation 94, 1647–1654 (1996).
Soeda, S. et al. An attempt to promote neo-vascularization by employing a newly synthesized inhibitor of protein tyrosine phosphatase. FEBS Lett. 524, 54–58 (2002).
Carr, A. N. et al. Tyrosine phosphatase inhibition augments collateral blood flow in a rat model of peripheral vascular disease. Am. J. Physiol. Heart Circ. Physiol. 287, H268–H276 (2004).
Eichmann, A., Le Noble, F., Autiero, M. & Carmeliet, P. Guidance of vascular and neural network formation. Curr. Opin. Neurobiol. 15, 108–115 (2005).
Klagsbrun, M. & Eichmann, A. A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis. Cytokine Growth Factor Rev. 16, 535–548 (2005).
Johnson, K. G. & Van Vactor, D. Receptor protein tyrosine phosphatases in nervous system development. Physiol. Rev. 83, 1–24 (2003).
Chagnon, M. J., Uetani, N. & Tremblay, M. L. Functional significance of the LAR receptor protein tyrosine phosphatase family in development and diseases. Biochem. Cell Biol. 82, 664–675 (2004).
Miao, H., Burnett, E., Kinch, M., Simon, E. & Wang, B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nature Cell Biol. 2, 62–69 (2000).
van Huijsduijnen, R. H., Bombrun, A. & Swinnen, D. Selecting protein tyrosine phosphatases as drug targets. Drug Discov. Today 7, 1013–1019 (2002).
Bialy, L. & Waldmann, H. Inhibitors of protein tyrosine phosphatases: next-generation drugs? Angew Chem. Int. Ed. Engl. 44, 3814–3839 (2005).
Johnson, T. O., Ermolieff, J. & Jirousek, M. R. Protein tyrosine phosphatase 1B inhibitors for diabetes. Nature Rev. Drug Discov. 1, 696–709 (2002).
Liang, F., Lee, S. Y., Liang, J., Lawrence, D. S. & Zhang, Z. Y. The role of protein-tyrosine phosphatase 1B in integrin signaling. J. Biol. Chem. 280, 24857–24863 (2005).
Liu, G. et al. Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor. J. Med. Chem. 46, 4232–4235 (2003).
Lund, I. K. et al. Structure-based design of selective and potent inhibitors of protein-tyrosine phosphatase β. J. Biol. Chem. 279, 24226–24235 (2004).
Imhof, D. et al. Design and biological evaluation of linear and cyclic phosphopeptide ligands of the N-terminal SH2 domain of protein tyrosine phosphatase SHP-1. J. Med. Chem. 48, 1528–1539 (2005). Modification of a natural phosphopeptide ligand of the N-terminal SH2 domain of SHP1 identified cyclic derivatives which bound with high affinity to the domain, but only poorly activated SHP1. Such ligands represent a novel class of inhibitors for the SH-domain PTPs that might be developed into novel types of drugs.
Tonks, N. K. Redox redux: revisiting PTPs and the control of cell signaling. Cell 121, 667–670 (2005).
Rhee, S. G. et al. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr. Opin. Cell Biol. 17, 183–189 (2005).
Sablina, A. A. et al. The antioxidant function of the p53 tumor suppressor. Nature Med. 11, 1306–1313 (2005).
Dube, N. et al. Genetic ablation of protein tyrosine phosphatase 1B accelerates lymphomagenesis of p53-null mice through the regulation of B-cell development. Cancer Res. 65, 10088–10095 (2005).
Denu, J. M. & Tanner, K. G. Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry 37, 5633–5642 (1998). First chemical analysis of the PTP reversible oxidation state evoked by mild H 2 O 2 treatment.
Salmeen, A. et al. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 423, 769–773 (2003).
Barrett, W. C. et al. Regulation of PTP1B via glutathionylation of the active site cysteine 215. Biochemistry 38, 6699–6705 (1999).
Barrett, D. M. et al. Inhibition of protein-tyrosine phosphatases by mild oxidative stresses is dependent on S-nitrosylation. J. Biol. Chem. 280, 14453–14461 (2005).
Meng, T. C., Fukada, T. & Tonks, N. K. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol. Cell 9, 387–399 (2002).
Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K. & Finkel, T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995).
Lee, S. R., Kwon, K. S., Kim, S. R. & Rhee, S. G. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J. Biol. Chem. 273, 15366–15372 (1998). First demonstration that reversible PTP oxidation occurs in intact cells as a consequence of growth factor stimulation.
Mahadev, K., Zilbering, A., Zhu, L. & Goldstein, B. J. Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade. J. Biol. Chem. 276, 21938–21942 (2001).
Singh, D. K. et al. The strength of receptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal. Cell 121, 281–293 (2005).
Gross, S. et al. Inactivation of protein-tyrosine phosphatases as mechanism of UV-induced signal transduction. J. Biol. Chem. 274, 26378–26386 (1999).
Persson, C. et al. Preferential oxidation of the second phosphatase domain of receptor-like PTP-α revealed by an antibody against oxidized protein tyrosine phosphatases. Proc. Natl Acad. Sci. USA 101, 1886–1891 (2004).
Choi, M. H. et al. Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature 435, 347–353 (2005).
Groen, A. et al. Differential oxidation of protein-tyrosine phosphatases. J. Biol. Chem. 280, 10298–10304 (2005).
Elson, A. & Leder, P. Protein-tyrosine phosphatase ε. An isoform specifically expressed in mouse mammary tumors initiated by v-Ha-ras or neu. J. Biol. Chem. 270, 26116–26122 (1995).
Matozaki, T. et al. Molecular cloning of a human transmembrane-type protein tyrosine phosphatase and its expression in gastrointestinal cancers. J. Biol. Chem. 269, 2075–2081 (1994).
Noguchi, T. et al. Inhibition of cell growth and spreading by stomach cancer-associated protein-tyrosine phosphatase-1 (SAP-1) through dephosphorylation of p130cas. J. Biol. Chem. 276, 15216–15224 (2001).
Takada, T. et al. Induction of apoptosis by stomach cancer-associated protein-tyrosine phosphatase-1. J. Biol. Chem. 277, 34359–34366 (2002).
Konishi, N. et al. Overexpression of leucocyte common antigen (LAR) P-subunit in thyroid carcinomas. Br. J. Cancer 88, 1223–1228 (2003).
Kulas, D. T., Goldstein, B. J. & Mooney, R. A. The transmembrane protein-tyrosine phosphatase LAR modulates signaling by multiple receptor tyrosine kinases. J. Biol. Chem. 271, 748–754 (1996).
Levea, C. M., McGary, C. T., Symons, J. R. & Mooney, R. A. PTP LAR expression compared to prognostic indices in metastatic and non-metastatic breast cancer. Breast Cancer Res. Treat. 64, 221–228 (2000).
Bjorge, J. D., Pang, A. & Fujita, D. J. Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines. J. Biol. Chem. 275, 41439–41446 (2000).
Wiener, J. R. et al. Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression. J. Natl Cancer Inst. 86, 372–378 (1994).
Dube, N., Cheng, A. & Tremblay, M. L. The role of protein tyrosine phosphatase 1B in Ras signaling. Proc. Natl Acad. Sci. USA 101, 1834–1839 (2004).
Buckley, D. A., Cheng, A., Kiely, P. A., Tremblay, M. L. & O'Connor, R. Regulation of insulin-like growth factor type I (IGF-I) receptor kinase activity by protein tyrosine phosphatase 1B (PTP-1B) and enhanced IGF-I-mediated suppression of apoptosis and motility in PTP-1B-deficient fibroblasts. Mol. Cell. Biol. 22, 1998–2010 (2002).
Somani, A. K., Bignon, J. S., Mills, G. B., Siminovitch, K. A. & Branch, D. R. Src kinase activity is regulated by the SHP-1 protein-tyrosine phosphatase. J. Biol. Chem. 272, 21113–21119 (1997).
Krautwald, S., Buscher, D., Kummer, V., Buder, S. & Baccarini, M. Involvement of the protein tyrosine phosphatase SHP-1 in Ras-mediated activation of the mitogen-activated protein kinase pathway. Mol. Cell. Biol. 16, 5955–5963 (1996).
Yip, S. S. et al. Up-regulation of the protein tyrosine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression. Int. J. Cancer 88, 363–368 (2000).
Zanke, B. et al. A hematopoietic protein tyrosine phosphatase (HePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome 1q32.1. Leukemia 8, 236–244 (1994).
Saxena, M., Williams, S., Tasken, K. & Mustelin, T. Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphatase. Nature Cell Biol. 1, 305–310 (1999).
Work in the authors' laboratories is supported by grants from the Swedish Cancer Society (Cancerfonden) the Deutsche Krebshilfe (F.D.B.) and Karolinska Institutet (A.Ö.) the Swedish Research Council (C.H and A.Ö.), the Deutsche Forschungsgemeinschaft (F.D.B.), the Deutsche Krebshilfe (F.D.B.), and the German Ministry for Education and Research (F.D.B.). We are grateful to the colleagues mentioned in the text for sharing with us their unpublished results, and to A. Uecker and C. H. Heldin for critical reading of the manuscript.
The authors declare no competing financial interests.
National Cancer Institute
- Immunoglobulin-like domain
Protein domain of approximately 100 amino-acids that was originally identified in antibodies. Structural features include 7–10 β–strands and an internal disulphide bridge. One or more of these domains commonly occur in the extracellular parts of growth-factor receptors and other transmembrane cell surface proteins, where they are involved in protein–protein interactions.
- Fibronectin type III domain
Protein domain with structural similarities to immunoglobulin-like domains, but lacking the internal disulphide. This domain is found in extracellular-matrix proteins, cell-surface receptors and enzymes, and often contains surface-exposed stretches of amino acids that are involved in protein–protein interactions, such as the prototypical RGD sequence in fibronectin that mediates integrin binding.
- K M
The Michaelis constant, KM, is defined as the substrate concentration at which half the maximum reaction velocity is attained. A small KM indicates that the enzyme requires only a small amount of substrate to become saturated, and a large KM indicates the need for high substrate concentrations to achieve maximum reaction velocity. The substrate with the lowest KM on which the enzyme acts is frequently assumed to be the enzyme's natural substrate.
- Substrate-trapping PTP
Variants of PTPs that have been experimentally altered so that they still bind their substrates but do not dephosphorylate them, which allows the identification of PTP substrates. This is most commonly achieved by substituting the active site cysteine residue with a serine (C/S mutant), or by substituting the conserved aspartic acid residue in the active site with an alanine residue (D/A mutant).
M5 subgroup of acute myeloid leukaemia of the French–American–British group-classification system.
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Östman, A., Hellberg, C. & Böhmer, F. Protein-tyrosine phosphatases and cancer. Nat Rev Cancer 6, 307–320 (2006). https://doi.org/10.1038/nrc1837
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