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Growth Factor Regulation of Kinases

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Data Mining in Structural Biology

Part of the book series: Ernst Schering Research Foundation Workshop ((SCHERING FOUND,volume 34))

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Abstract

Many important cellular events, including cell growth, differentiation, migration, and apoptosis, are regulated by external stimuli that the cell receives from its environment. Such signals come from direct interactions between receptors in the plasma membrane and components in the extracellular matrix or on other cells, as well as from interactions between cellular receptors and soluble growth regulatory factors. Several growth stimulatory factors, or cytokines, exert their effects by binding to protein tyrosine kinase receptors, whereas others bind to so-called cytokine receptors, which are devoid of kinase activity but which interact with cytoplasmic tyrosine kinases. Another important family of cytokines is the transforming growth factor-β (TGF-β) family; these factors have important roles in pattern formation during embryonal development and often inhibit cell growth via binding to protein serine/threonine kinase receptors.

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References

  • Akiyoshi S, Inoue H, Hanai J, Kusanagi K, Nemoto N, Miyazono K, and Kawabata M (1999) c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with Smads. J Biol Chem 274:35269–35277

    Article  PubMed  CAS  Google Scholar 

  • Bitzer M, von Gersdorff G, Liang D, Dominguez-Rosales A, Beg AA, Rojkind M, and Bottinger EP (2000) A mechanism of suppression of TGF-β/SMAD signaling by NF-K B/RelA. Genes Dev 14:187–197

    PubMed  CAS  Google Scholar 

  • Bos JL (1997) Ras-like GTPases. Biochim Biophys Acta 1333:M19–M31

    PubMed  CAS  Google Scholar 

  • Boström H, Willetts K, Pekny M, Levéen P, Lindahl P, Hedstrand H, Pekna M, Hellström M, Gebre-Medhin S, Schalling M, Nilsson M, Kurland S, Törnell J, Heath JK, and Betsholtz C (1996) PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 85:863–873

    Article  PubMed  Google Scholar 

  • Brodin G, Ähgren A, ten Dijke P, Heldin C-H, and Heuchel R (2000) Efficient TGF-β induction of the Smad7 gene requires co-operation between AP-1, Sp1 and Smad proteins on the mouse Smad7 promoter. J Biol Chem 275:29023–29030

    Article  PubMed  CAS  Google Scholar 

  • Chiarugi P, Cirri P, Raugei G, Camici G, Dolfí F, Berti A, and Ramponi G (1995) PDGF receptor as a specific in vivo target for low M r phosphotyros-ine protein phosphatase. FEBS Lett 372:49–53

    Article  PubMed  CAS  Google Scholar 

  • Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, and Akhurst RJ (1996) TGFβl inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 86:531–542

    Article  PubMed  CAS  Google Scholar 

  • DeMali KA, Balciunaite E, and Kazlauskas A (1999) Integrins enhance platelet-derived growth factor (PDGF)-dependent responses by altering the signal relay enzymes that are recruited to the PDGF β receptor. J Biol Chem 274:19551–19558

    Article  PubMed  CAS  Google Scholar 

  • Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, and Greenberg ME (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275:661–665

    Article  PubMed  CAS  Google Scholar 

  • Ekman S, Rupp Thuresson E, Heldin C-H, and Rönnstrand L (1999) Increased mitogenicity of an aβ heterodimeric PDGF receptor complex correlates with lack of RasGAP binding. Oncogene 18:2481–2488

    Article  PubMed  CAS  Google Scholar 

  • Eriksson A, Siegbahn A, Westermark B, Heldin C-H, and Claesson-Welsh L (1992) PDGF a- and β-receptors activate unique and common signal transduction pathways. EMBO J 11:543–550

    PubMed  CAS  Google Scholar 

  • Fambrough D, McClure K, Kazlauskas A, and Lander ES (1999) Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes. Cell 97:727–741

    Article  PubMed  CAS  Google Scholar 

  • Feng XH, Zhang Y, Wu RY, and Derynck R (1998) The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for Smad3 in TGF-β-induced transcriptional activation. Genes Dev 12:2153–2163

    Article  PubMed  CAS  Google Scholar 

  • Hahn SA, Schutte M, Hoque ATMS, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, and Kern SE (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271:350–353

    Article  PubMed  CAS  Google Scholar 

  • Hansen K, Johnell M, Siegbahn A, Rorsman C, Engström U, Wernstedt C, Heldin C-H, and Rönnstrand L (1996) Mutation of a Src phosphorylation site in the PDGF β-receptor leads to increased PDGF-stimulated Chemotaxis but decreased mitogenesis. EMBO J 15:5299–5313

    PubMed  CAS  Google Scholar 

  • Hata A, Lagna G, Massagué J, and Hemmati-Brivanlou A (1998) Smad6 inhibits BMP/Smadl signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12:186–197

    Article  PubMed  CAS  Google Scholar 

  • Hata A, Lo RS, Wotton D, Lagna G, and Massagué J (1997) Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4. Nature 388:82–87

    Article  PubMed  CAS  Google Scholar 

  • Hawkins PT, Eguinoa A, Qiu R-G, Stokoe D, Cooke FT, Walters R, Wennström S, Claesson-Welsh L, Evans T, Symons M, and Stephens L (1995) PDGF stimulates an increase in GTP-Rac via activation of phos-phoinositide 3-kinase. Curr Biol 5:393–403

    Article  PubMed  CAS  Google Scholar 

  • Hayashi H, Abdullah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MAJ, Wrana JL, and Falb D (1997) The MAD-re-lated protein Smad7 associates with the TGFβ receptor and functions as an antagonist of TGFβ signaling. Cell 89:1165–1173

    Article  PubMed  CAS  Google Scholar 

  • Heidaran MA, Pierce JH, Jensen RA, Matsui T, and Aaronson SA (1990) Chimeric a- and β-platelet-derived growth factor (PDGF) receptors define three immunoglobulin-like domains of the α-PDGF receptor that determine PDGF-A A binding specificity. J Biol Chem 265:18741–18744

    PubMed  CAS  Google Scholar 

  • Heidaran MA, Beeler JF, Yu J-C, Ishibashi T, LaRochelle WJ, Pierce JH, and Aaronson SA (1993) Differences in substrate specificities of a and β platelet-derived growth factor (PDGF) receptors. J Biol Chem 268:9287–9295

    PubMed  CAS  Google Scholar 

  • Heldin C-H, Miyazono K, and ten Dijke P (1997) TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471

    Article  PubMed  CAS  Google Scholar 

  • Heldin C-H, and Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283–1316

    PubMed  CAS  Google Scholar 

  • Heldin C-H, östman A, and Rönnstrand L (1998) Signal transduction via platelet-derived growth factor receptors. Biochem Biophys Acta 1378:F79-F113

    PubMed  CAS  Google Scholar 

  • Heuchel R, Berg A, Tallquist M, Åhlén K, Reed RK, Rubin K, Claesson-Welsh L, Heldin C-H, and Soriano P (1999) Platelet-derived growth factor β receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3′ kinase signaling. Proc Natl Acad Sci USA 96:11410–11415

    Article  PubMed  CAS  Google Scholar 

  • Hooshmand-Rad R, Claesson-Welsh L, Wennström S, Yokote K, Siegbahn A, and Heldin C-H (1997) Involvement of phosphatidylinositide 3′-kinase and Rac in platelet-derived growth factor-induced actin reorganization and Chemotaxis. Exp Cell Res 234:434–441

    Article  PubMed  CAS  Google Scholar 

  • Hooshmand-Rad R, Hájková L, Klint P, Karlsson R, Vanhaesebroeck B, Claesson-Welsh L, and Heldin C-H (2000) The PI 3-kinase isoforms p110α and p110β have differential roles in PDGF- and insulin-mediated signaling. J Cell Sci 113:207–214

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, and Miyazono K (1997) Smad6 inhibits signalling by the TGF-β superfamily. Nature 389:622–626

    Article  PubMed  CAS  Google Scholar 

  • Janknecht R, Wells NJ, and Hunter T (1998) TGF-β-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes Dev 12:2114–2119

    Article  PubMed  CAS  Google Scholar 

  • Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, and Evan G (1997) Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 385:544–548

    Article  PubMed  CAS  Google Scholar 

  • Kazlauskas A, and Cooper JA (1989) Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins. Cell 58:1121–1133

    Article  PubMed  CAS  Google Scholar 

  • Kelly JD, Haldeman BA, Grant FJ, Murray MJ, Seifert RA, Bowen-Pope DF, Cooper JA, and Kazlauskas A (1991) Platelet-derived growth factor (PDGF) stimulates PDGF receptor subunit dimerization and intersubunit trans-phosphorylation. J Biol Chem 266:8987–8992

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Koyama H, Nishizawa Y, Hosoi M, Fukumoto S, Kogawa K, Shioi A, and Morii H (1996) The fumagillin analogue TNP-470 inhibits DNA synthesis of vascular smooth muscle cells stimulated by platelet-derived growth factor and insulin-like growth factor-I — possible involvement of cyclin-de-pendent kinase 2. Circ Res 79:757–764

    Article  PubMed  CAS  Google Scholar 

  • Kretzschmar M, Doody J, Timokhina I, and Massagué J (1999) A mechanism of repression of TGFβ/Smad signaling by oncogenic Ras. Genes Dev 13:804–816

    Article  PubMed  CAS  Google Scholar 

  • Levéen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, and Betsholtz C (1994) Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev 8:1875–1887

    Article  PubMed  Google Scholar 

  • Li X, Pontén A, Aase K, Karlsson L, Abramsson A, Uutela M, Bäckström G, Hellström M, Boström H, Li H, Soriano P, Betsholtz C, Heldin C-H, Alitalo K, östman A, and Eriksson U (2000) PDGF-C is a new protease-activated ligand for the PDGF ot-receptor. Nature Cell Biol 2:302–309

    Article  PubMed  CAS  Google Scholar 

  • Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, and Zhou Q (1999) The Ski oncoprotein interacts with the Smad proteins to repress TGFβ signaling. Genes Dev 13:2196–2206

    Article  PubMed  CAS  Google Scholar 

  • Mohammadi M, Dikic I, Sorokin A, Burgess WH, Jaye M, and Schlessinger J (1996a) Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction. Mol Cell Biol 16:977–989

    PubMed  CAS  Google Scholar 

  • Mohammadi M, Schlessinger J, and Hubbard SR (1996b) Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism. Cell 86:577–587

    Article  PubMed  CAS  Google Scholar 

  • Morén A, Itoh S, Moustakas A, ten Dijke P, and Heldin C-H (2000) Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4. Oncogene 19:4396–4404

    Article  PubMed  Google Scholar 

  • Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kаnо T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K, Nishida E, and Hagiwara M (1996) A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem 271:13675–13679

    Article  PubMed  CAS  Google Scholar 

  • Nagarajan RP, Liu J, and Chen Y (1999) Smad3 inhibits transforming growth factor-beta and activin signaling by competing with Smad4 for FAST-2 binding. J Biol Chem 274:31229–31235

    Article  PubMed  CAS  Google Scholar 

  • Nakao A, Afrakhte M, Morén A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin N-E, Heldin C-H, and ten Dijke P (1997) Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 389:631–635

    Article  PubMed  CAS  Google Scholar 

  • Naldini L, Vigna E, Ferracini R, Longati P, Gandino L, Prat M, and Comoglio PM (1991) The tyrosine kinase encoded by the MET proto-oncogene is activated by autophosphorylation. Mol Cell Biol 11:1793–1803

    PubMed  CAS  Google Scholar 

  • Oft M, Heider KH, and Beug H (1998) TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 8:1243–1252

    Article  PubMed  CAS  Google Scholar 

  • Omura T, Heldin C-H, and östman A (1997) Immunoglobulin-like domain 4-mediated receptor-receptor interactions contribute to platelet-derived growth factor-induced receptor dimerization. J Biol Chem 272:12676–12682

    Article  PubMed  CAS  Google Scholar 

  • Pawson T, and Scott JD (1997) Signaling through scaffold, anchoring, and adaptor proteins. Science 278:2075–2080

    Article  PubMed  CAS  Google Scholar 

  • Piek E, Heldin C-H, and ten Dijke P (1999) Specificity, diversity, and regulation in TGF-β superfamily signaling. FASEB J 13:2105–2124

    PubMed  CAS  Google Scholar 

  • Raftery LA, Twombly V, Wharton K, and Gelbart WM (1995) Genetic screens to identify elements of the decapentaplegic signaling pathway in Droso-phila. Genetics 139:241–254

    PubMed  CAS  Google Scholar 

  • Robson MC, Phillips LG, Thomason A, Robson LE, and Pierce GF (1992) Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet 339:23–25

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, and Downward J (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370:527–532

    Article  PubMed  CAS  Google Scholar 

  • Romashkova JA, and Makarov SS (1999) NF-KB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401:86–90

    Article  PubMed  CAS  Google Scholar 

  • Rönnstrand L, Siegbahn A, Rorsman C, Johnell M, Hansen K, and Heldin C-H (1999) Overactivation of phospholipase C-yl renders platelet-derived growth factor β-receptor-expressing cells independent of the phosphatidyli-nositol 3-kinase pathway for Chemotaxis. J Biol Chem 274:22089–22094

    Article  PubMed  Google Scholar 

  • Savage C, Das P, Finelli AL, Townsend SR, Sun C-Y, Baird SE, and Padgett RW (1996) Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor β pathway components. Proc Natl Acad Sci USA 93:790–794

    Article  PubMed  CAS  Google Scholar 

  • Shibuya H, Yamaguchi K, Shirakabe K, Tonegawa A, Gotoh Y, Ueno N, Irie K, Nishida E, and Matsumoto K (1996) TAB1: An activator of the TAK1 MAPKKK in TGF-β signal transduction. Science 272:1179–1182

    Article  PubMed  CAS  Google Scholar 

  • Shirakabe K, Yamaguchi K, Shibuya H, Irie K, Matsuda S, Moriguchi T, Gotoh Y, Matsumoto K, and Nishida E (1997) TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem 272:8141–8144

    Article  PubMed  CAS  Google Scholar 

  • Shulman T, Sauer FG, Jackman RM, Chang CN, and Landolfi NF (1997) An antibody reactive with domain 4 of the platelet-derived growth factor β receptor allows BB binding while inhibiting proliferation by impairing receptor dimerization. J Biol Chem 272:17400–17404

    Article  PubMed  CAS  Google Scholar 

  • Siegbahn A, Hammacher A, Westermark B, and Heldin C-H (1990) Differential effects of the various isoforms of platelet-derived growth factor on Chemotaxis of fibroblasts, monocytes, and granulocytes. J Clin Invest 85:916–920

    Article  PubMed  CAS  Google Scholar 

  • Stroschein SL, Wang W, Zhou SL, Zhou Q, and Luo KX (1999) Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 286:771–774

    Article  PubMed  CAS  Google Scholar 

  • Sun Y, Liu X, Eaton EN, Lane WS, Lodish HF, and Weinberg RA (1999) Interaction of the Ski oncoprotein with Smad3 regulates TGF-β signaling. Mol Cell 4:499–509

    Article  PubMed  CAS  Google Scholar 

  • ten Dijke P, Miyazono K, and Heldin C-H (2000) Signaling inputs converge on nuclear effectors in TGF-β signaling. Trends Biol Sci 25:64–70

    Article  Google Scholar 

  • Twamley-Stein GM, Pepperkok R, Ansorge W, and Courtneidge SA (1993) The Src family tyrosine kinases are required for platelet-derived growth factor-mediated signal transduction in NIH 3T3 cells. Proc Natl Acad Sci USA 90:7696–7700

    Article  PubMed  CAS  Google Scholar 

  • Ulloa L, Doody J, and Massagué J (1999) Inhibition of transforming growth factor-β/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397:710–713

    Article  PubMed  CAS  Google Scholar 

  • Valius M, and Kazlauskas A (1993) Phospholipase C-γ1 and phosphatidyli-nositol 3 kinase are the downstream mediators of the PDGF receptor’s mi-togenic signal. Cell 73:321–334

    Article  PubMed  CAS  Google Scholar 

  • Vanhaesebroeck B, Leevers SJ, Panayotou G, and Waterfield MD (1997) Phos-phoinositide 3-kinases: a conserved family of signal transducers. TIBS 22:267–272

    PubMed  CAS  Google Scholar 

  • White MF, Shoelson SE, Keutmann H, and Kahn CR (1988) A cascade of tyrosine autophosphorylation in the β-subunit activates the phosphotransferase of the insulin receptor. J Biol Chem 263:2969–2980

    PubMed  CAS  Google Scholar 

  • Wotton D, Lo RS, Lee S, and Massagué J (1999) A Smad transcriptional corepressor. Cell 97:29–39

    Article  PubMed  CAS  Google Scholar 

  • Wrana JL, Attisano L, Wieser R, Ventura F, and Massagué J (1994) Mechanism of activation of the TGF-β receptor. Nature 370:341–347

    Article  PubMed  CAS  Google Scholar 

  • Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, and Matsumoto K (1995) Identification of a member of the МAРKKK family as a potential mediator of TGF-β signal transduction. Science 270:2008–2011

    Article  PubMed  CAS  Google Scholar 

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  1. C.-H. Heldin
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Editors and Affiliations

  1. Department of Biophysical Chemistry, Max-Planck-Institute for Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany

    I. Schlichting

  2. Research Laboratories, Schering AG, Müllerstrasse 178, 13342, Berlin, Germany

    U. Egner

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© 2001 Springer-Verlag Berlin Heidelberg

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Heldin, CH. (2001). Growth Factor Regulation of Kinases. In: Schlichting, I., Egner, U. (eds) Data Mining in Structural Biology. Ernst Schering Research Foundation Workshop, vol 34. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-04645-6_1

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  • DOI: https://doi.org/10.1007/978-3-662-04645-6_1

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