Protein tyrosine phosphatases: from genes, to function, to disease

Nature Reviews Molecular Cell Biology - Tập 7 Số 11 - Trang 833-846 - 2006
Nicholas K. Tonks1
1Cold Spring Harbor Laboratory 1 Bungtown Road Cold Spring Harbor, New York 11724 USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

Heinrich, R., Neel, B. G. & Rapoport, T. A. Mathematical models of protein kinase signal transduction. Mol. Cell 9, 957–970 (2002).

Hornberg, J. J. et al. Principles behind the multifarious control of signal transduction. ERK phosphorylation and kinase/phosphatase control. FEBS J. 272, 244–258 (2005).

Cohen, P. T. W. in Overview of Protein Serine/Threonine Phosphatases (eds Arino, J. & Alexander D. R.) (Spring-Verlag, Berlin, 2004).

Epstein, J. A. & Neel, B. G. Signal transduction: an eye on organ development. Nature 426, 238–239 (2003).

Wiggan, O., Bernstein, B. W. & Bamburg, J. R. A phosphatase for cofilin to be HAD. Nature Cell Biol. 7, 8–9 (2005).

Hughes, W. E., Cooke, F. T. & Parker, P. J. Sac phosphatase domain proteins. Biochem. J. 350, 337–352 (2000).

Alonso, A. et al. Protein tyrosine phosphatases in the human genome. Cell 117, 699–711 (2004).

Andersen, J. N. et al. A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB J. 18, 8–30 (2004).

Andersen, J. N. et al. Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol. Cell. Biol. 21, 7117–7136 (2001). References 7, 8 and 9 provide comprehensive overviews of the structure, regulation and function of the PTP superfamily.

Cousin, W., Courseaux, A., Ladoux, A., Dani, C. & Peraldi, P. 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 (2004).

Buist, A. et al. Restoration of potent protein-tyrosine phosphatase activity into the membrane-distal domain of receptor protein-tyrosine phosphatase α. Biochemistry 38, 914–922 (1999).

Felberg, J. & Johnson, P. Characterization of recombinant CD45 cytoplasmic domain proteins. Evidence for intramolecular and intermolecular interactions. J. Biol. Chem. 273, 17839–17845 (1998).

Streuli, M., Krueger, N. X., Thai, T., Tang, M. & Saito, H. Distinct functional roles of the two intracellular phosphatase like domains of the receptor-linked protein tyrosine phosphatases LCA and LAR. EMBO J. 9, 2399–2407 (1990).

Blanchetot, C., Tertoolen, L. G., Overvoorde, J. & den Hertog, J. Intra- and intermolecular interactions between intracellular domains of receptor protein-tyrosine phosphatases. J. Biol. Chem. 277, 47263–47269 (2002).

Jiang, G., den Hertog, J. & Hunter, T. Receptor-like protein tyrosine phosphatase α homodimerizes on the cell surface. Mol. Cell. Biol. 20, 5917–5929 (2000).

Garton, A. J., Burnham, M. R., Bouton, A. H. & Tonks, N. K. Association of PTP-PEST with the SH3 domain of p130cas; a novel mechanism of protein tyrosine phosphatase substrate recognition. Oncogene 15, 877–885 (1997).

Pulido, R., Zuniga, A. & Ullrich, A. 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 (1998).

Guan, K. L., Broyles, S. S. & Dixon, J. E. A Tyr/Ser protein phosphatase encoded by vaccinia virus. Nature 350, 359–362 (1991).

Poon, R. Y. & Hunter, T. Dephosphorylation of Cdk2 Thr160 by the cyclin-dependent kinase-interacting phosphatase KAP in the absence of cyclin. Science 270, 90–93 (1995).

Schumacher, M. A., Todd, J. L., Rice, A. E., Tanner, K. G. & Denu, J. M. Structural basis for the recognition of a bisphosphorylated MAP kinase peptide by human VHR protein phosphatase. Biochemistry 41, 3009–3017 (2002).

Wen, Y., Yue, Z. & Shatkin, A. J. Mammalian capping enzyme binds RNA and uses protein tyrosine phosphatase mechanism. Proc. Natl Acad. Sci. USA 95, 12226–12231 (1998).

Begley, M. J. & Dixon, J. E. The structure and regulation of myotubularin phosphatases. Curr. Opin. Struct. Biol. 15, 614–620 (2005). Excellent review of the myotubularin subfamily of phosphatases.

Wishart, M. J. & Dixon, J. E. Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains. Trends Biochem. Sci. 23, 301–306 (1998).

Wishart, M. J. & Dixon, J. E. The archetype STYX/dead-phosphatase complexes with a spermatid mRNA-binding protein and is essential for normal sperm production. Proc. Natl Acad. Sci. USA 99, 2112–2117 (2002).

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).

Alessi, D. R., Sakamoto, K. & Bayascas, J. R. LKB1-dependent signaling pathways. Annu. Rev. Biochem. 75, 137–163 (2006).

Shannon, K. & Van Etten, R. A. JAKing up hematopoietic proliferation. Cancer Cell 7, 291–293 (2005).

Laporte, J., Bedez, F., Bolino, A. & Mandel, J. L. Myotubularins, a large disease-associated family of cooperating catalytically active and inactive phosphoinositides phosphatases. Hum. Mol. Genet. 12, R285–R292 (2003).

Kim, S. A., Vacratsis, P. O., Firestein, R., Cleary, M. L. & Dixon, J. E. Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase. Proc. Natl Acad. Sci. USA 100, 4492–4497 (2003).

Robinson, F. L. & Dixon, J. E. The phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot–Marie–Tooth disease. J. Biol. Chem. 280, 31699–31707 (2005).

Mochizuki, Y. & Majerus, P. W. Characterization of myotubularin-related protein 7 and its binding partner, myotubularin-related protein 9. Proc. Natl Acad. Sci. USA 100, 9768–9773 (2003).

Azzedine, H. et al. Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot–Marie–Tooth disease associated with early-onset glaucoma. Am. J. Hum. Genet. 72, 1141–1153 (2003).

Begley, M. J. et al. Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase. Proc. Natl Acad. Sci. USA 103, 927–932 (2006).

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).

Weiss, A. & Schlessinger, J. Switching signals on or off by receptor dimerization. Cell 94, 277–280 (1998).

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).

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).

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). This is a highly significant study, which, together with reference 91, provides important insights into dimerization as a potential mechanism for the regulation of receptor PTP function.

Majeti, R. et al. An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell 103, 1059–1070 (2000).

Hermiston, M. L., Tan, A. L., Gupta, V. A., Majeti, R. & Weiss, A. The juxtamembrane wedge negatively regulates CD45 function in B cells. Immunity 23, 635–647 (2005).

Hermiston, M. L., Xu, Z. & Weiss, A. CD45: a critical regulator of signaling thresholds in immune cells. Annu. Rev. Immunol. 21, 107–137 (2003).

Xu, Z. & Weiss, A. Negative regulation of CD45 by differential homodimerization of the alternatively spliced isoforms. Nature Immunol. 3, 764–771 (2002).

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). An important study, characterizing the regulation of a receptor PTP by ligand binding.

Pariser, H., Perez-Pinera, P., Ezquerra, L., Herradon, G. & Deuel, T. F. Pleiotrophin stimulates tyrosine phosphorylation of β-adducin through inactivation of the transmembrane receptor protein tyrosine phosphatase β/ζ. Biochem. Biophys. Res. Commun. 335, 232–239 (2005).

Tamura, H., Fukada, M., Fujikawa, A. & Noda, M. Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP. Neurosci. Lett. 399, 33–38 (2006).

Niisato, K. et al. Age-dependent enhancement of hippocampal long-term potentiation and impairment of spatial learning through the Rho-associated kinase pathway in protein tyrosine phosphatase receptor type Z-deficient mice. J. Neurosci. 25, 1081–1088 (2005).

Eswarakumar, V. P., Lax, I. & Schlessinger, J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 16, 139–149 (2005).

Aricescu, A. R., McKinnell, I. W., Halfter, W. & Stoker, A. W. Heparan sulfate proteoglycans are ligands for receptor protein tyrosine phosphatase σ. Mol. Cell. Biol. 22, 1881–1892 (2002).

Fox, A. N. & Zinn, K. The heparan sulfate proteoglycan syndecan is an in vivo ligand for the Drosophila LAR receptor tyrosine phosphatase. Curr. Biol. 15, 1701–1711 (2005).

Johnson, K. G. et al. The HSPGs Syndecan and Dallylike bind the receptor phosphatase LAR and exert distinct effects on synaptic development. Neuron 49, 517–531 (2006). An elegant study, together with reference 49, characterizing the regulation of the receptor PTP LAR by ligand binding at neuromuscular junctions.

O'Grady, P., Thai, T. C. & Saito, H. The laminin–nidogen complex is a ligand for a specific splice isoform of the transmembrane protein tyrosine phosphatase LAR. J. Cell Biol. 141, 1675–1684 (1998).

Brady-Kalnay, S. M., Flint, A. J. & Tonks, N. K. Homophilic binding of PTPmu, a receptor-type protein tyrosine phosphatase, can mediate cell–cell aggregation. J. Cell Biol. 122, 961–972 (1993).

Zondag, G. C. M. et al. Homophilic interactions mediated by receptor tyrosine phosphatases μ and κ. J. Biol. Chem. 270, 14247–14250 (1995).

Yang, T. et al. Leukocyte antigen-related protein tyrosine phosphatase receptor: a small ectodomain isoform functions as a homophilic ligand and promotes neurite outgrowth. J. Neurosci. 23, 3353–3363 (2003).

Yang, T., Yin, W., Derevyanny, V. D., Moore, L. A. & Longo, F. M. Identification of an ectodomain within the LAR protein tyrosine phosphatase receptor that binds homophilically and activates signalling pathways promoting neurite outgrowth. Eur. J. Neurosci. 22, 2159–2170 (2005).

Finkel, T. Oxidant signals and oxidative stress. Curr. Opin. Cell Biol. 15, 247–254 (2003). An excellent overview of the targets and functions of ROS.

Lambeth, J. D. NOX enzymes and the biology of reactive oxygen. Nature Rev. Immunol. 4, 181–189 (2004). A comprehensive review of the NOX family of enzymes.

Rhee, S. G. et al. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr. Opin. Cell Biol. 17, 183–189 (2005). An excellent review of the role of hydrogen peroxide as a second messenger.

den Hertog, J., Groen, A. & van der Wijk, T. Redox regulation of protein-tyrosine phosphatases. Arch. Biochem. Biophys. 434, 11–15 (2005).

Salmeen, A. & Barford, D. Functions and mechanisms of redox regulation of cysteine-based phosphatases. Antioxid. Redox Signal 7, 560–577 (2005).

Tonks, N. K. Redox redux: revisiting PTPs and the control of cell signaling. Cell 121, 667–670 (2005). This review, together with references 59 and 60, provides a comprehensive overview of the regulation of PTP function by reversible oxidation.

Salmeen, A. et al. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 423, 769–773 (2003). An important paper that, together with reference 118, provides structural insights into the effects of ROS on the active site of PTP1B. The data suggest an explanation, at the molecular level, of how oxidation can be harnessed as a mechanism for reversible regulation of PTP function.

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).

van der Wijk, T., Overvoorde, J. & den Hertog, J. H2O2-induced intermolecular disulfide bond formation between receptor protein-tyrosine phosphatases. J. Biol. Chem. 279, 44355–44361 (2004).

Groen, A. et al. Differential oxidation of protein-tyrosine phosphatases. J. Biol. Chem. 280, 10298–10304 (2005).

Goldstein, B. J., Mahadev, K., Wu, X., Zhu, L. & Motoshima, H. Role of insulin-induced reactive oxygen species in the insulin signaling pathway. Antioxid. Redox Signal 7, 1021–1031 (2005).

Martyn, K. D., Frederick, L. M., von Loehneysen, K., Dinauer, M. C. & Knaus, U. G. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal. 18, 69–82 (2006).

Kamata, H. et al. Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120, 649–661 (2005).

Duranteau, J., Chandel, N. S., Kulisz, A., Shao, Z. & Schumacker, P. T. Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes. J. Biol. Chem. 273, 11619–11624 (1998).

Ostman, A., Hellberg, C. & Bohmer, F. D. Protein-tyrosine phosphatases and cancer. Nature Rev. Cancer 6, 307–320 (2006). A comprehensive review of the function of PTPs in tumorigenesis.

Kristjansdottir, K. & Rudolph, J. Cdc25 phosphatases and cancer. Chem. Biol. 11, 1043–1051 (2004).

Cully, M., You, H., Levine, A. J. & Mak, T. W. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nature Rev. Cancer 6, 184–192 (2006).

Bentires-Alj, M., Kontaridis, M. I. & Neel, B. G. Stops along the RAS pathway in human genetic disease. Nature Med. 12, 283–285 (2006).

Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genet. 36, 337–338 (2004).

Smyth, D. et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53, 3020–3023 (2004).

Begovich, A. B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).

Carlton, V. E. et al. PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis. Am. J. Hum. Genet. 77, 567–581 (2005).

Kyogoku, C. et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am. J. Hum. Genet. 75, 504–507 (2004).

Wu, J. et al. Identification of substrates of human protein tyrosine phosphatase PTPN22. J. Biol. Chem. 281, 11002–11010 (2006).

Vang, T. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nature Genet. 37, 1317–1319 (2005).

Andersen, J. N. & Tonks, N. K. in Protein Tyrosine Phosphatase-Based Therapeutics: Lessons from PTP1B (eds Arino, J. & Alexander, D. R.) (Spring-Verlag, Berlin, 2004). An overview of drug-discovery efforts targetting members of the PTP superfamily, in particular PTP1B.

Liu, G. Technology evaluation: ISIS-113715, Isis. Curr. Opin. Mol. Ther. 6, 331–336 (2004).

Zinker, B. A. et al. PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proc. Natl Acad. Sci. USA 99, 11357–11362 (2002).

Wiesmann, C. et al. Allosteric inhibition of protein tyrosine phosphatase 1B. Nature Struct. Mol. Biol. 11, 730–737 (2004).

Xie, Y. et al. Protein-tyrosine phosphatase (PTP) wedge domain peptides: a novel approach for inhibition of PTP function and augmentation of protein-tyrosine kinase function. J. Biol. Chem. 281, 16482–16492 (2006).

Sapieha, P. S. et al. Receptor protein tyrosine phosphatase σ inhibits axon regrowth in the adult injured CNS. Mol. Cell Neurosci. 28, 625–635 (2005).

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).

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). The first description of the use of 'substrate trapping' mutants, an approach now applied widely in the field to define the substrate specificity of members of the PTP superfamily.

Shintani, T. et al. Eph receptors are negatively controlled by protein tyrosine phosphatase receptor type O. Nature Neurosci. 9, 761–769 (2006).

Tertoolen, L. G. et al. Dimerization of receptor protein-tyrosine phosphatase α in living cells. BMC Cell Biol. 2, 8 (2001).

Jiang, G. et al. Dimerization inhibits the activity of receptor-like protein-tyrosine phosphatase-α. Nature 401, 606–610 (1999). This is a highly significant study, which, together with reference 38, provides important insights into dimerization as a potential mechanism for the regulation of receptor PTP function.

Blanchetot, C., Tertoolen, L. G. & den Hertog, J. Regulation of receptor protein-tyrosine phosphatase α by oxidative stress. EMBO J. 21, 493–503 (2002).

van der Wijk, T., Blanchetot, C., Overvoorde, J. & den Hertog, J. Redox-regulated rotational coupling of receptor protein-tyrosine phosphatase α dimers. J. Biol. Chem. 278, 13968–13974 (2003).

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).

Nakamura, M. et al. Novel tumor suppressor loci on 6q22–23 in primary central nervous system lymphomas. Cancer Res. 63, 737–741 (2003).

Wang, Z. et al. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304, 1164–1166 (2004).

Jacob, S. T. & Motiwala, T. Epigenetic regulation of protein tyrosine phosphatases: potential molecular targets for cancer therapy. Cancer Gene Ther. 12, 665–672 (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).

Oka, T. et al. Gene silencing of the tyrosine phosphatase SHP 1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res. 62, 6390–6394 (2002).

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).

Yeh, S. H. et al. Genetic characterization of Fas-associated phosphatase-1 as a putative tumor suppressor gene on chromosome 4q21.3 in hepatocellular carcinoma. Clin. Cancer Res. 12, 1097–1108 (2006).

Garcia, J. M. et al. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer 41, 117–124 (2004).

Xu, S., Furukawa, T., Kanai, N., Sunamura, M. & Horii, A. Abrogation of DUSP6 by hypermethylation in human pancreatic cancer. J. Hum. Genet. 50, 159–167 (2005).

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).

Tartaglia, M. & Gelb, B. D. Noonan syndrome and related disorders: genetics and pathogenesis. Annu. Rev. Genomics Hum. Genet. 6, 45–68 (2005).

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).

Salmond, R. J. & Alexander, D. R. SHP2 forecast for the immune system: fog gradually clearing. Trends Immunol. 27, 154–160 (2006). This review, together with references 105 and 106, provides a comprehensive overview of the structure, regulation and function of SHP2 — the first PTP oncoprotein.

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).

Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genet. 34, 148–150 (2003).

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).

Chan, R. J. et al. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 105, 3737–3742 (2005).

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).

Schubbert, S. et al. Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Blood 106, 311–317 (2005).

Digilio, M. C. et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am. J. Hum. Genet. 71, 389–394 (2002).

Kontaridis, M. I., Swanson, K. D., David, F. S., Barford, D. & Neel, B. G. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J. Biol. Chem. 281, 6785–6792 (2006).

Lim, K. L., Kolatkar, P. R., Ng, K. P., Ng, C. H. & Pallen, C. J. Interconversion of the kinetic identities of the tandem catalytic domains of receptor-like protein-tyrosine phosphatase PTPα by two point mutations is synergistic and substrate-dependent. J. Biol. Chem. 273, 28986–28993 (1998).

van Montfort, R. L., Congreve, M., Tisi, D., Carr, R. & Jhoti, H. Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. Nature 423, 773–777 (2003). An important paper that, together with reference 62, provides structural insights into the effects of ROS on the active site of PTP1B. The data suggest an explanation, at the molecular level, of how oxidation can be harnessed as a mechanism for reversible regulation of PTP function.

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). An important paper that provided the first demonstration of reversible oxidation and inactivation of a defined PTP in response to a physiological stimulus.

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).

Meng, T. C., Buckley, D. A., Galic, S., Tiganis, T. & Tonks, N. K. Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B. J. Biol. Chem. 279, 37716–37725 (2004).

Meng, T. C., Fukada, T. & Tonks, N. K. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol. Cell 9, 387–399 (2002). An analysis of the regulation of PTP function by reversible oxidation, which introduces the use of a modified in-gel phosphatase assay to measure PTP oxidation. The study highlights the role of oxidation of SHP2 in regulating platelet-derived growth factor (PDGF) receptor signalling.

Kwon, J. et al. Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76–ADAP. EMBO J. 24, 2331–2341 (2005).

Chen, C. H. et al. Reactive oxygen species generation is involved in epidermal growth factor receptor transactivation through the transient oxidization of Src homology 2-containing tyrosine phosphatase in endothelin-1 signaling pathway in rat cardiac fibroblasts. Mol. Pharmacol. 69, 1347–1355 (2006).

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).

Xu, Y., Shao, Y., Voorhees, J. J. & Fisher, G. J. Oxidative inhibition of receptor type protein tyrosine phosphatase κ by ultraviolet irradiation activates EGFR in human keratinocytes. J. Biol. Chem. 18 July 2006 (doi: 10.1074/jbc.M602355200).

Wu, R. F. et al. Subcellular targeting of oxidants during endothelial cell migration. J. Cell Biol. 171, 893–904 (2005).

Levinthal, D. J. & Defranco, D. B. Reversible oxidation of ERK-directed protein phosphatases drives oxidative toxicity in neurons. J. Biol. Chem. 280, 5875–5883 (2005).

Kwon, J. et al. Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc. Natl Acad. Sci. USA 101, 16419–16424 (2004).

Seo, J. H., Ahn, Y., Lee, S. R., Yeol Yeo, C. & Chung Hur, K. The major target of the endogenously generated reactive oxygen species in response to insulin stimulation is phosphatase and tensin homolog and not phosphoinositide-3 kinase (PI-3 kinase) in the PI-3 kinase/Akt pathway. Mol. Biol. Cell 16, 348–357 (2005).

Chiarugi, P. et al. Two vicinal cysteines confer a peculiar redox regulation to low molecular weight protein tyrosine phosphatase in response to platelet-derived growth factor receptor stimulation. J. Biol. Chem. 276, 33478–33487 (2001).

Chiarugi, P. et al. Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J. Cell Biol. 161, 933–944 (2003).

Nimnual, A. S., Taylor, L. J. & Bar-Sagi, D. Redox-dependent downregulation of Rho by Rac. Nature Cell Biol. 5, 236–241 (2003).