• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Dec 15, 1998; 17(24): 7337–7350.
PMCID: PMC1171079

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.

Abstract

Protein kinases and phosphatases regulate the activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by controlling the phosphorylation of specific residues. We report the physical and functional association of ERK1/2 with the PTP-SL and STEP protein tyrosine phosphatases (PTPs). Upon binding, the N-terminal domains of PTP-SL and STEP were phosphorylated by ERK1/2, whereas these PTPs dephosphorylated the regulatory phosphotyrosine residues of ERK1/2 and inactivated them. A sequence of 16 amino acids in PTP-SL was identified as being critical for ERK1/2 binding and termed kinase interaction motif (KIM) (residues 224-239); it was shown to be required for phosphorylation of PTP-SL by ERK1/2 at Thr253. Co-expression of ERK2 with catalytically active PTP-SL in COS-7 cells impaired the EGF-induced activation of ERK2, whereas a PTP-SL mutant, lacking PTP activity, increased the ERK2 response to EGF. This effect was dependent on the presence of the KIM on PTP-SL. Furthermore, ERK1/2 activity was downregulated in 3T3 cells stably expressing PTP-SL. Our findings demonstrate the existence of a conserved ERK1/2 interaction motif within the cytosolic non-catalytic domains of PTP-SL and STEP, which is required for the regulation of ERK1/2 activity and for phosphorylation of the PTPs by these kinases. Our findings suggest that PTP-SL and STEP act as physiological regulators of the ERK1/2 signaling pathway.

Full Text

The Full Text of this article is available as a PDF (556K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adachi M, Sekiya M, Isobe M, Kumura Y, Ogita Z, Hinoda Y, Imai K, Yachi A. Molecular cloning and chromosomal mapping of a human protein-tyrosine phosphatase LC-PTP. Biochem Biophys Res Commun. 1992 Aug 14;186(3):1607–1615. [PubMed]
  • Alessi DR, Gomez N, Moorhead G, Lewis T, Keyse SM, Cohen P. Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines. Curr Biol. 1995 Mar 1;5(3):283–295. [PubMed]
  • Anderson NG, Maller JL, Tonks NK, Sturgill TW. Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase. Nature. 1990 Feb 15;343(6259):651–653. [PubMed]
  • Bardwell L, Cook JG, Chang EC, Cairns BR, Thorner J. Signaling in the yeast pheromone response pathway: specific and high-affinity interaction of the mitogen-activated protein (MAP) kinases Kss1 and Fus3 with the upstream MAP kinase kinase Ste7. Mol Cell Biol. 1996 Jul;16(7):3637–3650. [PMC free article] [PubMed]
  • Boulanger LM, Lombroso PJ, Raghunathan A, During MJ, Wahle P, Naegele JR. Cellular and molecular characterization of a brain-enriched protein tyrosine phosphatase. J Neurosci. 1995 Feb;15(2):1532–1544. [PubMed]
  • Braconi Quintaje S, Church DJ, Rebsamen M, Valloton MB, Hemmings BA, Lang U. Role of protein phosphatase 2A in the regulation of mitogen-activated protein kinase activity in ventricular cardiomyocytes. Biochem Biophys Res Commun. 1996 Apr 25;221(3):539–547. [PubMed]
  • Bult A, Zhao F, Dirkx R, Jr, Raghunathan A, Solimena M, Lombroso PJ. STEP: a family of brain-enriched PTPs. Alternative splicing produces transmembrane, cytosolic and truncated isoforms. Eur J Cell Biol. 1997 Apr;72(4):337–344. [PubMed]
  • Canagarajah BJ, Khokhlatchev A, Cobb MH, Goldsmith EJ. Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell. 1997 Sep 5;90(5):859–869. [PubMed]
  • Chajry N, Martin PM, Cochet C, Berthois Y. Regulation of p42 mitogen-activated-protein kinase activity by protein phosphatase 2A under conditions of growth inhibition by epidermal growth factor in A431 cells. Eur J Biochem. 1996 Jan 15;235(1-2):97–102. [PubMed]
  • Choi KY, Satterberg B, Lyons DM, Elion EA. Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. Cell. 1994 Aug 12;78(3):499–512. [PubMed]
  • Cobb MH, Goldsmith EJ. How MAP kinases are regulated. J Biol Chem. 1995 Jun 23;270(25):14843–14846. [PubMed]
  • Cobb MH, Boulton TG, Robbins DJ. Extracellular signal-regulated kinases: ERKs in progress. Cell Regul. 1991 Dec;2(12):965–978. [PMC free article] [PubMed]
  • Davis RJ. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [PubMed]
  • Dikic I, Schlessinger J, Lax I. PC12 cells overexpressing the insulin receptor undergo insulin-dependent neuronal differentiation. Curr Biol. 1994 Aug 1;4(8):702–708. [PubMed]
  • Doi K, Gartner A, Ammerer G, Errede B, Shinkawa H, Sugimoto K, Matsumoto K. MSG5, a novel protein phosphatase promotes adaptation to pheromone response in S. cerevisiae. EMBO J. 1994 Jan 1;13(1):61–70. [PMC free article] [PubMed]
  • Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686–7689. [PMC free article] [PubMed]
  • Fischer EH, Charbonneau H, Tonks NK. Protein tyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science. 1991 Jul 26;253(5018):401–406. [PubMed]
  • Fukuda M, Gotoh Y, Nishida E. Interaction of MAP kinase with MAP kinase kinase: its possible role in the control of nucleocytoplasmic transport of MAP kinase. EMBO J. 1997 Apr 15;16(8):1901–1908. [PMC free article] [PubMed]
  • Fukunaga R, Hunter T. MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J. 1997 Apr 15;16(8):1921–1933. [PMC free article] [PubMed]
  • Garton AJ, Tonks NK. PTP-PEST: a protein tyrosine phosphatase regulated by serine phosphorylation. EMBO J. 1994 Aug 15;13(16):3763–3771. [PMC free article] [PubMed]
  • Gonzalez FA, Seth A, Raden DL, Bowman DS, Fay FS, Davis RJ. Serum-induced translocation of mitogen-activated protein kinase to the cell surface ruffling membrane and the nucleus. J Cell Biol. 1993 Sep;122(5):1089–1101. [PMC free article] [PubMed]
  • Griswold-Prenner I, Carlin CR, Rosner MR. Mitogen-activated protein kinase regulates the epidermal growth factor receptor through activation of a tyrosine phosphatase. J Biol Chem. 1993 Jun 25;268(18):13050–13054. [PubMed]
  • Groom LA, Sneddon AA, Alessi DR, Dowd S, Keyse SM. Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase. EMBO J. 1996 Jul 15;15(14):3621–3632. [PMC free article] [PubMed]
  • Guan KL, Dixon JE. Bacterial and viral protein tyrosine phosphatases. Semin Cell Biol. 1993 Dec;4(6):389–396. [PubMed]
  • Hendriks W, Schepens J, Brugman C, Zeeuwen P, Wieringa B. A novel receptor-type protein tyrosine phosphatase with a single catalytic domain is specifically expressed in mouse brain. Biochem J. 1995 Jan 15;305(Pt 2):499–504. [PMC free article] [PubMed]
  • Her JH, Wu J, Rall TB, Sturgill TW, Weber MJ. Sequence of pp42/MAP kinase, a serine/threonine kinase regulated by tyrosine phosphorylation. Nucleic Acids Res. 1991 Jul 11;19(13):3743–3743. [PMC free article] [PubMed]
  • Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993 Nov;7(11):2135–2148. [PubMed]
  • Hsiao KM, Chou SY, Shih SJ, Ferrell JE., Jr Evidence that inactive p42 mitogen-activated protein kinase and inactive Rsk exist as a heterodimer in vivo. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5480–5484. [PMC free article] [PubMed]
  • Hunter T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell. 1995 Jan 27;80(2):225–236. [PubMed]
  • Jacoby T, Flanagan H, Faykin A, Seto AG, Mattison C, Ota I. Two protein-tyrosine phosphatases inactivate the osmotic stress response pathway in yeast by targeting the mitogen-activated protein kinase, Hog1. J Biol Chem. 1997 Jul 11;272(28):17749–17755. [PubMed]
  • Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem. 1995 Jul 14;270(28):16483–16486. [PubMed]
  • Kemp BE, Pearson RB. Protein kinase recognition sequence motifs. Trends Biochem Sci. 1990 Sep;15(9):342–346. [PubMed]
  • Keyse SM. An emerging family of dual specificity MAP kinase phosphatases. Biochim Biophys Acta. 1995 Mar 16;1265(2-3):152–160. [PubMed]
  • Kosako H, Gotoh Y, Matsuda S, Ishikawa M, Nishida E. Xenopus MAP kinase activator is a serine/threonine/tyrosine kinase activated by threonine phosphorylation. EMBO J. 1992 Aug;11(8):2903–2908. [PMC free article] [PubMed]
  • Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987 Oct 26;15(20):8125–8148. [PMC free article] [PubMed]
  • Kyriakis JM, Avruch J. Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem. 1996 Oct 4;271(40):24313–24316. [PubMed]
  • Lee RM, Cobb MH, Blackshear PJ. Evidence that extracellular signal-regulated kinases are the insulin-activated Raf-1 kinase kinases. J Biol Chem. 1992 Jan 15;267(2):1088–1092. [PubMed]
  • Lenormand P, Sardet C, Pagès G, L'Allemain G, Brunet A, Pouysségur J. Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J Cell Biol. 1993 Sep;122(5):1079–1088. [PMC free article] [PubMed]
  • Lewis T, Groom LA, Sneddon AA, Smythe C, Keyse SM. XCL100, an inducible nuclear MAP kinase phosphatase from Xenopus laevis: its role in MAP kinase inactivation in differentiated cells and its expression during early development. J Cell Sci. 1995 Aug;108(Pt 8):2885–2896. [PubMed]
  • Lombroso PJ, Murdoch G, Lerner M. Molecular characterization of a protein-tyrosine-phosphatase enriched in striatum. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7242–7246. [PMC free article] [PubMed]
  • Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. [PubMed]
  • Mauro LJ, Dixon JE. 'Zip codes' direct intracellular protein tyrosine phosphatases to the correct cellular 'address'. Trends Biochem Sci. 1994 Apr;19(4):151–155. [PubMed]
  • Millar JB, Buck V, Wilkinson MG. Pyp1 and Pyp2 PTPases dephosphorylate an osmosensing MAP kinase controlling cell size at division in fission yeast. Genes Dev. 1995 Sep 1;9(17):2117–2130. [PubMed]
  • Muda M, Theodosiou A, Gillieron C, Smith A, Chabert C, Camps M, Boschert U, Rodrigues N, Davies K, Ashworth A, et al. The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzymatic specificity. J Biol Chem. 1998 Apr 10;273(15):9323–9329. [PubMed]
  • Mukhopadhyay NK, Price DJ, Kyriakis JM, Pelech S, Sanghera J, Avruch J. An array of insulin-activated, proline-directed serine/threonine protein kinases phosphorylate the p70 S6 kinase. J Biol Chem. 1992 Feb 15;267(5):3325–3335. [PubMed]
  • Nakielny S, Cohen P, Wu J, Sturgill T. MAP kinase activator from insulin-stimulated skeletal muscle is a protein threonine/tyrosine kinase. EMBO J. 1992 Jun;11(6):2123–2129. [PMC free article] [PubMed]
  • Ogata M, Sawada M, Fujino Y, Hamaoka T. cDNA cloning and characterization of a novel receptor-type protein tyrosine phosphatase expressed predominantly in the brain. J Biol Chem. 1995 Feb 3;270(5):2337–2343. [PubMed]
  • Payne DM, Rossomando AJ, Martino P, Erickson AK, Her JH, Shabanowitz J, Hunt DF, Weber MJ, Sturgill TW. Identification of the regulatory phosphorylation sites in pp42/mitogen-activated protein kinase (MAP kinase). EMBO J. 1991 Apr;10(4):885–892. [PMC free article] [PubMed]
  • Pulido R, Serra-Pagès C, Tang M, Streuli M. The LAR/PTP delta/PTP sigma subfamily of transmembrane protein-tyrosine-phosphatases: multiple human LAR, PTP delta, and PTP sigma isoforms are expressed in a tissue-specific manner and associate with the LAR-interacting protein LIP.1. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11686–11690. [PMC free article] [PubMed]
  • Racke FK, Lewandowska K, Goueli S, Goldfarb AN. Sustained activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway is required for megakaryocytic differentiation of K562 cells. J Biol Chem. 1997 Sep 12;272(37):23366–23370. [PubMed]
  • Rouyez MC, Boucheron C, Gisselbrecht S, Dusanter-Fourt I, Porteu F. Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway. Mol Cell Biol. 1997 Sep;17(9):4991–5000. [PMC free article] [PubMed]
  • Saito H, Streuli M. Molecular characterization of protein tyrosine phosphatases. Cell Growth Differ. 1991 Jan;2(1):59–65. [PubMed]
  • Sarcevic B, Erikson E, Maller JL. Purification and characterization of a mitogen-activated protein kinase tyrosine phosphatase from Xenopus eggs. J Biol Chem. 1993 Nov 25;268(33):25075–25083. [PubMed]
  • Saxena M, Williams S, Gilman J, Mustelin T. Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP). J Biol Chem. 1998 Jun 19;273(25):15340–15344. [PubMed]
  • Scimeca JC, Nguyen TT, Filloux C, Van Obberghen E. Nerve growth factor-induced phosphorylation cascade in PC12 pheochromocytoma cells. Association of S6 kinase II with the microtubule-associated protein kinase, ERK1. J Biol Chem. 1992 Aug 25;267(24):17369–17374. [PubMed]
  • Sharma E, Lombroso PJ. A neuronal protein tyrosine phosphatase induced by nerve growth factor. J Biol Chem. 1995 Jan 6;270(1):49–53. [PubMed]
  • Sharma E, Zhao F, Bult A, Lombroso PJ. Identification of two alternatively spliced transcripts of STEP: a subfamily of brain-enriched protein tyrosine phosphatases. Brain Res Mol Brain Res. 1995 Aug;32(1):87–93. [PubMed]
  • Shiozuka K, Watanabe Y, Ikeda T, Hashimoto S, Kawashima H. Cloning and expression of PCPTP1 encoding protein tyrosine phosphatase. Gene. 1995 Sep 11;162(2):279–284. [PubMed]
  • Smith DB, Johnson KS. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene. 1988 Jul 15;67(1):31–40. [PubMed]
  • Sun H, Charles CH, Lau LF, Tonks NK. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell. 1993 Nov 5;75(3):487–493. [PubMed]
  • Tonks NK, Neel BG. From form to function: signaling by protein tyrosine phosphatases. Cell. 1996 Nov 1;87(3):365–368. [PubMed]
  • Traverse S, Gomez N, Paterson H, Marshall C, Cohen P. Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem J. 1992 Dec 1;288(Pt 2):351–355. [PMC free article] [PubMed]
  • Traverse S, Seedorf K, Paterson H, Marshall CJ, Cohen P, Ullrich A. EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr Biol. 1994 Aug 1;4(8):694–701. [PubMed]
  • Trowbridge IS. CD45. A prototype for transmembrane protein tyrosine phosphatases. J Biol Chem. 1991 Dec 15;266(35):23517–23520. [PubMed]
  • Walton KM, Dixon JE. Protein tyrosine phosphatases. Annu Rev Biochem. 1993;62:101–120. [PubMed]
  • Ward Y, Gupta S, Jensen P, Wartmann M, Davis RJ, Kelly K. Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1. Nature. 1994 Feb 17;367(6464):651–654. [PubMed]
  • Waskiewicz AJ, Flynn A, Proud CG, Cooper JA. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 1997 Apr 15;16(8):1909–1920. [PMC free article] [PubMed]
  • Whalen AM, Galasinski SC, Shapiro PS, Nahreini TS, Ahn NG. Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase. Mol Cell Biol. 1997 Apr;17(4):1947–1958. [PMC free article] [PubMed]
  • Wilson IA, Niman HL, Houghten RA, Cherenson AR, Connolly ML, Lerner RA. The structure of an antigenic determinant in a protein. Cell. 1984 Jul;37(3):767–778. [PubMed]
  • Wu J, Lau LF, Sturgill TW. Rapid deactivation of MAP kinase in PC12 cells occurs independently of induction of phosphatase MKP-1. FEBS Lett. 1994 Oct 10;353(1):9–12. [PubMed]
  • Wurgler-Murphy SM, Maeda T, Witten EA, Saito H. Regulation of the Saccharomyces cerevisiae HOG1 mitogen-activated protein kinase by the PTP2 and PTP3 protein tyrosine phosphatases. Mol Cell Biol. 1997 Mar;17(3):1289–1297. [PMC free article] [PubMed]
  • Yamada A, Streuli M, Saito H, Rothstein DM, Schlossman SF, Morimoto C. Effect of activation of protein kinase C on CD45 isoform expression and CD45 protein tyrosine phosphatase activity in T cells. Eur J Immunol. 1990 Aug;20(8):1655–1660. [PubMed]
  • Yang SH, Yates PR, Whitmarsh AJ, Davis RJ, Sharrocks AD. The Elk-1 ETS-domain transcription factor contains a mitogen-activated protein kinase targeting motif. Mol Cell Biol. 1998 Feb;18(2):710–720. [PMC free article] [PubMed]
  • Zanke B, Suzuki H, Kishihara K, Mizzen L, Minden M, Pawson A, Mak TW. Cloning and expression of an inducible lymphoid-specific, protein tyrosine phosphatase (HePTPase). Eur J Immunol. 1992 Jan;22(1):235–239. [PubMed]
  • Zhang F, Strand A, Robbins D, Cobb MH, Goldsmith EJ. Atomic structure of the MAP kinase ERK2 at 2.3 A resolution. Nature. 1994 Feb 24;367(6465):704–711. [PubMed]
  • Zhao Z, Tan Z, Diltz CD, You M, Fischer EH. Activation of mitogen-activated protein (MAP) kinase pathway by pervanadate, a potent inhibitor of tyrosine phosphatases. J Biol Chem. 1996 Sep 6;271(36):22251–22255. [PubMed]
  • Zheng CF, Guan KL. Dephosphorylation and inactivation of the mitogen-activated protein kinase by a mitogen-induced Thr/Tyr protein phosphatase. J Biol Chem. 1993 Aug 5;268(22):16116–16119. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...