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Characterization of Growth Factor Receptor-Directed Protein Tyrosine Phosphatases

  • Conference paper
EGF Receptor in Tumor Growth and Progression

Part of the book series: Ernst Schering Research Foundation Workshop ((SCHERING FOUND,volume 19))

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Abstract

Dimerization of growth factor receptor tyrosine kinases (RTK) (Heldin 1995) leads in turn to a mutual phosphorylation of two receptor monomers at multiple tyrosine residues. This process, commonly designated as “autophosphorylation” is the initial and a crucial event of growth factor signaling, which is followed by initiation of a multitude of downstream signaling chains (Ullrich and Schlessinger 1990; Fantl et al. 1993). RTK autophosphorylation serves two purposes: (1) It regulates the activity of the RTK positively, albeit to a different extent for different receptor species. Determination of the three-dimensional structure of the catalytic center of the insulin receptor has recently shed some light on the structural basis for the pronounced activation of this RTK by autophosphorylation (Hubbard et al. 1994). Tyrosine 1162 in the unphosphorylated form sterically blocks access to the peptide substrate and the ATP binding sites. In the phosphorylated form it is expected to become disengaged from the active center and to allow access of the substrates. In terms of homology it is possible that such a mechanism might operate similarly in other RTK. (2) Autophosphorylation creates binding sites for intracellular proteins possessing phosphotyrosine binding domains such as SH2 or PTB domains (Pawson 1995).

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References

  • Ahmad F, Considine RV, Goldstein BJ (1995) Increased abundance of the receptor-type protein-tyrosine phosphatase LAR accounts for the elevated insulin receptor dephosphorylating activity in adipose tissue of obese human subjects. J Clin Invest 95:2806–2812

    Article  PubMed  CAS  Google Scholar 

  • Aicher B (1996) Untersuchungen zur Spezifität und Regulation der Phosphotyrosinphosphatasen LAR und PTPα. Thesis. University of Munich

    Google Scholar 

  • Barford D, Jia ZC, Tonks NK (1995) Protein-tyrosine phosphatases take-off. Nat Struct Biol 2:1043–1053

    Article  PubMed  CAS  Google Scholar 

  • Berti A, Rigacci S, Raugei G, Deglinnocenti D, Ramponi G (1994) Inhibition of cellular response to platelet-derived growth factor by low M(r) phosphotyrosine protein phosphatase overexpression. FEBS Lett 349:7–12

    Article  PubMed  CAS  Google Scholar 

  • Blakesley VA, Kato H, Roberts CT, Leroith D (1995) Mutation of a conserved amino acid residue (tryptophan 1173) in the tyrosine kinase domain of the IGF-I receptor abolishes autophosphorylation but does not eliminate biologic function. J Biol Chem 270:2764–2769

    Article  PubMed  CAS  Google Scholar 

  • Böhmer FD, Böhmer SA, Heldin CH (1993) The dephosphorylation characteristics of the receptors for epidermal growth factor and platelet-derived growth factor in Swiss 3T3-cell membranes suggest differential regulation of receptor signalling by endogenous protein-tyrosine phosphatases. FEBS Lett 331:276–280

    Article  PubMed  Google Scholar 

  • Böhmer FD, Böhmer A, Obermeier A, Ullrich A (1995) Use of selective tyrosine kinase blockers to monitor growth-factor receptor dephosphorylation in intact-cells. Anal Biochem 228:267–273

    Article  PubMed  Google Scholar 

  • Bouchard P, Zhao ZZ, Banville D, Dumas F, Fischer EH, Shen SH (1994) Phosphorylation and identification of a major tyrosine phosphorylation site in protein tyrosine phosphatase 1C. J Biol Chem 269:19585–19589

    PubMed  CAS  Google Scholar 

  • Brady-Kalnay SM, Tonks NK (1994) Identification of the homophilic binding site of the receptor protein tyrosine phosphatase PTP µ. J Biol Chem 269:28472–28477

    PubMed  CAS  Google Scholar 

  • Brady-Kalnay SM, Flint AJ, Tonks NK (1993) Homophilic binding of PTP-µ, a receptor-type protein tyrosine phosphatase, can mediate cell cell aggregation. J Cell Biol 122:961–972

    Article  PubMed  CAS  Google Scholar 

  • Celler JW, Luo XM, Gonez LJ, Böhmer FD (1995) mRNA expression of two transmembrane protein tyrosine phosphatases is modulated by growth factors and growth arrest in 3T3 fibroblasts. Biochem Biophys Res Commun 209:614–621

    Article  PubMed  CAS  Google Scholar 

  • Charbonneau H, Tonks NK (1992) 1002 phosphatases? Annu Rev Cell Biol 8:463–493

    Article  PubMed  CAS  Google Scholar 

  • Charbonneau H, Tonks NK, Kumar S, Diltz CD, Harrylock M, Cool DE, Krebs EG, Fischer EH, Walsh KA (1989) Human placenta protein-tyrosinephosphatase: amino acid sequence and relationship to a family of receptor-like proteins. Proc Natl Acad Sci USA 86:5252–5256

    Article  PubMed  CAS  Google Scholar 

  • Cho H, Krishnaraj R, Itoh M, Kitas E, Bannwarth W, Saito H, Walsh CT (1993) Substrate specificities of catalytic fragments of protein tyrosine phosphatases (HPTP beta, LAR, and CD45) toward phosphotyrosylpeptide substrates and thiophosphotyrosylated peptides as inhibitors. Protein Sci 2:977–984

    Article  PubMed  CAS  Google Scholar 

  • Cool DE, Tonks NK, Charbonneau H, Fischer EH, Krebs EG (1990) Expression of a human T- cell protein-tyrosine-phosphatase in baby hamster kidney cells. Proc Natl Acad Sci USA 87:7280–7284

    Article  PubMed  CAS  Google Scholar 

  • Cyster JG, Goodnow CC (1995) Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection. Immunity 2:13–24

    Article  PubMed  CAS  Google Scholar 

  • D’Ambrosio D, Hippen KL, Minskoff SA, Mellman I, Pani G, Siminovitch KA, Cambier JC (1995) Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by Fc gamma RIIB 1. Science 268:293–297

    Article  PubMed  Google Scholar 

  • Decker SJ (1993) Transmembrane signaling by epidermal growth factor receptors lacking autophosphorylation sites. J Biol Chem 268:9176–9179

    PubMed  CAS  Google Scholar 

  • DenHertog J, Tracy S, Hunter T (1994) Phosphorylation of receptor protein-tyrosine phosphatase alpha on Tyr789, a binding site for the SH3-SH2-SH3 adaptor protein GRB-2 in vivo. EMBO J 13:3020–3032

    CAS  Google Scholar 

  • DenHertog J, Sap J, Pals C, Schlessinger J, Kruijer W (1995) Stimulation of receptor protein-tyrosine phosphatase alpha activity and phosphorylation by phorbol ester. Cell Growth Differ 6:303–307

    CAS  Google Scholar 

  • Desai DM, Sap J, Schlessinger J, Weiss A (1993) Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase. Cell 73:541–554

    Article  PubMed  CAS  Google Scholar 

  • Dixon JE (1995) Structure and catalytic properties of protein-tyrosine phosphatases. Ann N Y Acad Sci 766:18–22

    Article  PubMed  CAS  Google Scholar 

  • Fantl WJ, Johnson DE, Williams LT (1993) Signalling by receptor tyrosine kinases. Annu Rev Biochem 62:453–481

    Article  PubMed  CAS  Google Scholar 

  • Feng GS, Pawson T (1994) Phosphotyrosine phosphatases with Sh2 domains — regulators of signal transduction. Trends Genet 10:54–58

    Article  PubMed  CAS  Google Scholar 

  • Feng GS, Hui CC, Pawson T (1993) SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science 259:1607–1611

    Article  PubMed  CAS  Google Scholar 

  • Flint AJ, Gebbink MF, Franza BJ, Hill DE, Tonks NK (1993) Multi-site phosphorylation of the protein tyrosine phosphatase, PTP 1 B: identification of cell cycle regulated and phorbol ester stimulated sites of phosphorylation. EMBO J 12:1937–1946

    PubMed  CAS  Google Scholar 

  • Garton AJ, Tonks NK (1994) PTP-PEST: a protein tyrosine phosphatase regulated by serine phosphorylation. EMBO J 13:3763–3771

    PubMed  CAS  Google Scholar 

  • Gebbink MFBG, Zondag GCM, Wubbolts RW, Beijersbergen RL, Vanetten I, Moolenaar WH (1993) Cell-cell adhesion mediated by a receptor-like protein tyrosine phosphatase. J Biol Chem 268:16101–16104

    PubMed  CAS  Google Scholar 

  • Hashimoto N, Feener EP, Zhang WR, Goldstein BJ (1992) Insulin receptor protein-tyrosine phosphatases — leukocyte common antigen-related rhosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain. J Biol Chem 267:13811–13814

    PubMed  CAS  Google Scholar 

  • Heldin CH (1995) Dimerization of cell surface receptors in signal transduction. Cell 80:213–223

    Article  PubMed  CAS  Google Scholar 

  • Hubbard SR, Wei L, Elis L, Hendrickson WA (1994) Crystal structure of the tyrosine kinase domain of the human insulin receptor. Nature 372:746–754

    Article  PubMed  CAS  Google Scholar 

  • Klinghoffer RA, Kazlauskas A (1995) Identification of a putative Syp substrate, the PDGF beta receptor. J Biol Chem 270:22208–22217

    Article  PubMed  CAS  Google Scholar 

  • Klingmuller U, Lorenz U, Cantley LC, Neel BG, Lodish HF (1995) Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80:72–738

    Article  Google Scholar 

  • Kovalenko M, Gazit A, Böhmer A, Rorsman C, Ronnstrand L, Heldin CH, Waltenberger J, Böhmer FD, Levitzki A (1994) Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. Cancer Res 54:6106–6114

    PubMed  CAS  Google Scholar 

  • Kulas DT, Zhang WR, Goldstein BJ, Furlanetto RW, Mooney RA (1995) Insulin receptor signaling is augmented by antisense inhibition of the protein tyrosine phosphatase LAR. J Biol Chem 270:2435–2438

    Article  PubMed  CAS  Google Scholar 

  • Kulas DT, Freund GG, Mooney RA (1996a) The transmembrane protein-tyrosine-phosphatase cd45 is associated with decreased insulin-receptor signaling. J Biol Chem 271:755–760

    Article  PubMed  CAS  Google Scholar 

  • Kulas DT, Goldstein BJ, Mooney RA (1996b) The transmembrane protein-tyrosine-phosphatase lar modulates signaling by multiple receptor tyrosine kinases. J Biol Chem 271:748–754

    Article  PubMed  CAS  Google Scholar 

  • Lammers R, Bossenmaier B, Cool DE, Tonks NK, Schlessinger J, Fischer EH, Ullrich A (1993) Differential activities of protein tyrosine phosphatases in intact cells. J Biol Chem 268:22456–22462

    PubMed  CAS  Google Scholar 

  • Lechleider RJ, Sugimoto S, Bennett AM, Kashishian AS, Cooper JA, Shoelson SE, Walsh CT, Neel BG (1993) Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine-1009, on the human platelet-derived growth factor receptor-beta. J Biol Chem 268:21478–21481

    PubMed  CAS  Google Scholar 

  • Levitzki A, Gazit A (1995) Tyrosine kinase inhibition: an approach to drug development. Science 267:1782–1788

    Article  PubMed  CAS  Google Scholar 

  • Li NX, Schlessinger J, Margolis B (1994) Autophosphorylation mutants of the EGF-receptor signal through auxiliary mechanisms involving SH2 domain proteins. Oncogene 9:3457–3465

    PubMed  CAS  Google Scholar 

  • Li W, Nishimura R, Kashishian A, Batzer AG, Kim WJH, Cooper JA, Schlessinger J (1994) A new function for a phosphotyrosine phosphatase — linking Grb2-SOS to a receptor tyrosine kinase. Mol Cell Biol 14:509–517

    Article  PubMed  CAS  Google Scholar 

  • Longo FM, Martignetti JA, Lebeau JM, Zhang JS, Barnes JP, Brosius J (1993) Leukocyte common antigen-related receptor-linked tyrosine phosphatase — regulation of messenger RNA expression. J Biol Chem 268:26503–26511

    PubMed  CAS  Google Scholar 

  • Mauro LJ, Dixon JE (1994) Zip codes direct intracellular protein tyrosine phosphatases to the correct cellular address. Trends Biochem Sci 19:151–155

    Article  PubMed  CAS  Google Scholar 

  • Milarski KL, Zhu GC, Pearl CG, McNamara DJ, Dobrusin EM, Maclean D, Thiemesefler A, Zhang ZY, Sawyer T, Decker SJ, Dixon JE, Saltiel AR (1993) Sequence specificity in recognition of the epidermal growth factor receptor by protein tyrosine phosphatase-1B. J Biol Chem 268: 23634–23639

    PubMed  CAS  Google Scholar 

  • Møller N, Mø11er K, Lammers R, Kharitonenkov A, Hoppe E, Wiberg F, Sures I, Ullrich A (1995) Selective down-regulation of the insulin receptor signal by protein-tyrosine phosphatases alpha, epsilon. J Biol Chem 270: 23126–23131

    Article  PubMed  Google Scholar 

  • Mooney RA, Freund GG, Way BA, Bordwell KL (1992) Expression of a transmembrane phospotyrosine phosphatase inhibits cellular response to platelet-derived growth factor and insulin-like growth factor. J Biol Chem 267:23443–23446

    PubMed  CAS  Google Scholar 

  • Ostman A, Yang Q, Tonks NK (1994) Expression of DEP-1, a receptor-like protein-tyrosine-phosphatase, is enhanced with increasing cell density. Proc Natl Acad Sci USA 91:9680–9684

    Article  PubMed  CAS  Google Scholar 

  • Pani G, Kozlowski M, Cambier JC, Mills GB, Siminovitch KA (1995) Identification of the tyrosine phosphatase ptp 1 c as a b cell antigen receptor-associated protein involved in the regulation of b cell signaling. J Exp Med 181:2077–2084

    Article  PubMed  CAS  Google Scholar 

  • Pawson T (1995) Protein modules and signalling networks. Nature 373:573–580

    Article  PubMed  CAS  Google Scholar 

  • Pei DH, Lorenz U, Klingmuller U, Neel BG, Walsh CT (1994) Intramolecular regulation of protein tyrosine phosphatase SH-PTP1: a new function for Src homology 2 domains. Biochemistry 33:15483–15493

    Article  PubMed  CAS  Google Scholar 

  • Peles E, Nativ M, Campbell PL, Sakurai T, Martinez R, Lev S, Clary DO, Schilling J, Barnea G, Plowman GD, Grumet M, Schlessinger J (1995) The carbonic anhydrase domain of receptor tyrosine phosphatase beta is a functional ligand for the axonal cell recognition molecule contactin. Ce11 82:251–260

    CAS  Google Scholar 

  • Peraldi P, Zhao ZH, Filloux C, Fischer EH, Vanobberghen E. (1994) Proteintyrosine-phosphatase 2C is phosphorylated and inhibited by 44-kDa mitogen-activated protein kinase. Proc Natl Acad Sci USA 91:5002–5006

    Article  PubMed  CAS  Google Scholar 

  • Rönnstrand L, Mori S, Arridsson AK, Eriksson A, Wernstedt C, Hellman U, Claessonwelsh L, Heldin CH (1992) Identification of 2 C-terminal autophosphorylation sites in the PDGF beta-receptor — involvement in the interaction with phospholipase-C-gamma. EMBO J 11:3911–3919

    PubMed  Google Scholar 

  • Rotin D, Margolis B, Mohammadi M, Daly RJ, Daum G, Li N, Fischer EH, Burgess WH, Ullrich A, Schlessinger J (1992) SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: identification of Tyr992 as the high-affinity binding site for SH2 domains of phospholipase Cγ. EMBO J 11:559–567

    PubMed  CAS  Google Scholar 

  • Sap J, Jiang YP, Friedlander D, Grumet M, Schlessinger J (1994) Receptor tyrosine phosphatase R-Ptp-kappa mediates homophilic binding. Mol Cell Biol 14:1–9

    PubMed  CAS  Google Scholar 

  • Schievella AR, Paige LA, Johnson KA, Hill DE, Erikson RL (1993) Protein tyrosine phosphatase-1 B undergoes mitosis-specific phosphorylation on serine. Cell Growth Differ 4:239–246

    PubMed  CAS  Google Scholar 

  • Serra-Pages C, Saito H, Streuli M (1994) Mutational analysis of proprotein processing, subunit association, and shedding of the LAR transmembrane protein tyrosine phosphatase. J Biol Chem 269:23632–23641

    PubMed  CAS  Google Scholar 

  • Stover DR, Walsh KA (1994) Protein-tyrosine phosphatase activity of CD45 is activated by sequential phosphorylation by two kinases. Mol Cell Biol 14:5523–5532

    PubMed  CAS  Google Scholar 

  • Su J, Batzer A, Sap J (1994) Receptor tyrosine phosphatase R-PTP-alpha is tyrosine-phosphorylated and associated with the adaptor protein Grb2. J Biol Chem 269:18731–18734

    PubMed  CAS  Google Scholar 

  • Sugimoto S, Lechleider RJ, Shoelson SE, Neel BG, Walsh CT (1993) Expression, purification, and characterization of SH2-containing protein tyrosine phosphatase, SH-PTP2. J Biol Chem 268:22771–22776

    PubMed  CAS  Google Scholar 

  • Tomic S, Greiser U, Lammers R, Kharitonenkov A, Imyanitov E, Ullrich A, Böhmer FD (1995) Association of SH2 domain protein tyrosine phosphatases with the epidermal growth factor receptor in human tumor cells. Phosphatidic acid activates receptor dephosphorylation by PTP1C. J Biol Chem 270:21277–21284

    Article  PubMed  CAS  Google Scholar 

  • Trachman JD, Huang J, Reem GH (1995) Activation of human thymocytes induces the phosphorylation of protein tyrosine phosphatase 1C. C R Acad Sci III 318:367–374

    Google Scholar 

  • Uchida T, Matozaki T, Noguchi T, Yamao T, Horita K, Suzuki T, Fujioka Y, Sakamoto C, Kasuga M (1994) Insulin stimulates the phosphorylation of Tyr(538) and the catalytic activity of Ptp 1 C, a protein tyrosine phosphatase with SRC homology-2 domains. J Biol Chem 269:12220–12228

    PubMed  CAS  Google Scholar 

  • Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203–212

    Article  PubMed  CAS  Google Scholar 

  • Valius M, Bazenet C, Kazlauskas A (1993) Tyrosines 1021 and 1009 are phosphorylation sites in the carboxy terminus of the platelet-derived growth factor receptor beta subunit and are required for binding of phospholipase C gamma and a 64-kilodalton protein, respectively. Mol Cell Biol 13:133–143

    PubMed  CAS  Google Scholar 

  • Vogel W, Lammers R, Huang J, Ullrich A (1993) Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science 259:1611–1614

    Article  PubMed  CAS  Google Scholar 

  • Yi T, Ihle JN (1993) Association of hematopoietic cell phosphatase with c-Kit after stimulation with c-Kit ligand. Mol Cell Biol 13:3350–3358

    PubMed  CAS  Google Scholar 

  • Yi TL, Mui ALF, Krystal G, Ihle JN (1993) Hematopoietic cell phosphatase associates with the interleukin-3 (IL-3) receptor-beta chain and down-regulates IL-3-induced tyrosine rhosphorylation and mitogenesis. Mol Cell Biol 13:7577–7586

    PubMed  CAS  Google Scholar 

  • Zhang ZY, Maclean D, McNamara DJ, Sawyer TK, Dixon JE (1994) Protein tyrosine phosphatase substrate specificity — size and phosphotyrosine positioning requirements in peptide substrates. Biochemistry 33:2285–2290

    Article  PubMed  CAS  Google Scholar 

  • Zhao ZH, Shen SH, Fischer EH (1993) Stimulation by phospholipids of a protein-tyrosine-phosphatase containing 2 src homology-2 domains. Proc Natl Acad Sci USA 90:4251–4255

    Article  PubMed  CAS  Google Scholar 

  • Zhao ZZ, Larocque R, Ho WT, Fischer EH, Shen SH (1994) Purification and characterization of Ptp2C, a widely distributed protein tyrosine phosphatase containing two Sh2 domains. J Biol Chem 269:8780–8785

    PubMed  CAS  Google Scholar 

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  1. F.-D. Böhmer
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Editors and Affiliations

  1. Research Laboratories of Schering AG, Experimental Oncology, Müllerstraße 178, 13342, Berlin, Germany

    R. B. Lichtner

  2. Berlex Biosciences, Protein Biochemistry and Biophysics, 94804-0099, Richmond, CA, USA

    R. N. Harkins

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Böhmer, FD. (1997). Characterization of Growth Factor Receptor-Directed Protein Tyrosine Phosphatases. In: Lichtner, R.B., Harkins, R.N. (eds) EGF Receptor in Tumor Growth and Progression. Ernst Schering Research Foundation Workshop, vol 19. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-03391-3_2

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  • DOI: https://doi.org/10.1007/978-3-662-03391-3_2

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