The EGF Receptor Signaling System

A Model for Growth Factor Receptor Signaling
  • Alan Wells
Part of the Endocrine Updates book series (ENDO, volume 17)


The receptor for epidermal growth factor (EGF) and related ligands (EGFR; also referred to as HER and c-erbB 1) is expressed on cells of many lineages. Receptor binding by at least five genetically distinct ligands activates the intrinsic kinase resulting in EGFR tyrosyl-phosphorylating itself and numerous intermediary effector molecules, including closely-related c-erbB receptor family members. This action initiates a multitude of signaling pathways, some of which attenuate receptor signaling. The integrated biological responses to EGFR signaling include mitogenesis or apoptosis, enhanced cell motility, protein secretion, and differentiation or dedifferentiation; the outcome depends both on the proteomic complement of cell and other operative extracellular signals. Implicated in organ morphogenesis, maintenance and repair, upregulated EGFR signaling also correlates with a wide variety of tumors, especially at progression to invasion and metastasis. Thus, EGFR and its resultant signals are therapeutic targets in cancer and wound healing treatments.


Epidermal Growth Factor Receptor Epidermal Growth Factor Human Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Gene Epidermal Growth Factor Receptor Signaling 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Sun H, Chen Z, Poppleton H, Scholich K, Mullenix J, Weipz GJ, Fulgham DL, Bertics PJ, Patel TB 1997 The juxtamembrane, cytosolic region of the epidermal growth factor receptot is involved in association with α-subunit of Gs. J Biol Chem 272: 5413–5420PubMedCrossRefGoogle Scholar
  2. 2.
    Stover DR, Becker M, Liebetanz J, Lydon NB 1995 Src phosphorylation of the epidermal growth factor receptor at novel sites mediates receptor interaction with src and p85a. J Biol Chem 270: 15591–15597PubMedCrossRefGoogle Scholar
  3. 3.
    Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, Neel BG, Birge RB, Fajardo JE, Chou MM, Hanafusa H, Schaffhausen B, Cantley LC 1993 SH2 domains recognize specific phosphopeptide sequences. Cell 72: 767–778PubMedCrossRefGoogle Scholar
  4. 4.
    Chen P, Xie H, Sekar MC, Gupta KB, Wells A 1994 Epidermal growth factor receptor-mediated cell motility: phospholipase C activity is required, but MAP kinase activity is not sufficient for induced cell movement. J Cell Biol 127: 847–857PubMedCrossRefGoogle Scholar
  5. 5.
    Flickinger TW, Maihle NJ, Kung H-J 1992 An alternatively processed mRNA from the avian c-erbB gene encodes a soluble, truncated form of the receptor that can block ligand-dependent transformation. Mol Cell Biol 12: 883–893PubMedGoogle Scholar
  6. 6.
    Marti U, Wells A 2000 The nuclear accumulation of a variant epidermal growth factor receptor ( EGFR) lacking the transmembrane domain requires co-expression of a full length EGFR. Mol Cell Biol Res Com 3: 8–14CrossRefGoogle Scholar
  7. 7.
    Sampson JH, Crotty LE, Lee S, Archer GE, Ashley DM, Wkstrand CJ, Hale LP, Small C, Dranoff G, Friedman AH, Friedman HS, Bigner DD 2000 Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors. Proc Natl Acad Sci (USA) 97: 7053–7058CrossRefGoogle Scholar
  8. 8.
    Nishikawa R, Ji X-D, Harmon R, Lazar CS, Gill GN, Cavenee WK, Huang H-JS 1994 A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci (USA) 91: 7727–7730CrossRefGoogle Scholar
  9. 9.
    Carraway KL, Cantley LC 1994 A neu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell 78: 5–8PubMedCrossRefGoogle Scholar
  10. 10.
    Haley J, Whittle M, Bennett P, Kinchington K, Ullrich A, Waterfield MD 1987 The human EGF receptor gene: structure of the 110kb locus and identification of sequences regulating its transcription. Oncogene Res 1: 375–396PubMedGoogle Scholar
  11. 11.
    Ishii S, Imamoto F, Yamanashi Y, Toyoshima K, Yamamoto T 1987 Characterization of the promoter region of the human c-erbB-2 protooncogene. Proc Natl Acad Sci (USA) 84: 4374–4378CrossRefGoogle Scholar
  12. 12.
    Shiraha H, Gupta K, Drabik KA, Wells A 2000 Aging fibroblasts present reduced epidermal growth factor ( EGF) responsiveness due to preferential loss of EGF receptors. J Biol Chem. 275: 19343–19351.PubMedCrossRefGoogle Scholar
  13. 13.
    Ludes-Meyers JH, Subler MA, Shivakumar CV, Munoz RM, Jiang P, Bigger JE, Brown DR, Deb SP, Deb S 1996 Transcriptional activation of the human epidermal growth factor receptor promoter by human p53. Mol Cell Biol 16: 6009–6019PubMedGoogle Scholar
  14. 14.
    Marti U, Burwen SJ, Jones AL 1989 Biological effects of epidermal growth factor, with emphasis on the gastrointestinal tract and liver: an update. Hepatology 9: 126–138PubMedCrossRefGoogle Scholar
  15. 15.
    DePotter CR, Quatacker J 1993 The p185erbB2 protein is localized on cell organelles involved in cell motility. Clin Exp Metastas 11: 453–461CrossRefGoogle Scholar
  16. 16.
    Hernandez-Sotomayor SMT, Artega CL, Soler C, Carpenter G 1993 Epidermal growth factor stimulates substrate-selective protein-tyrosine phosphatase activity. Proc Natl Acad Sci (USA) 90: 7691–7695CrossRefGoogle Scholar
  17. 17.
    Reddy CC, Wells A, Lauffenburger DA 1996 Receptor-mediated effects on ligand availability influence relative mitogenic potencies of epidermal growth factor and transforming growth factor a. J Cell Physiol 166: 512–522PubMedCrossRefGoogle Scholar
  18. 19.
    Dong J, Opresko LK, Dempsey PJ, Lauffenburger DA, Coffey RJ, Wiley HS 1999 Metalloprotease-mediated ligand release regulates autocrine signaling through the epidermal growth factor receptor. Proc Natl Acad Sci (USA) 96: 6235–6240CrossRefGoogle Scholar
  19. 20.
    Tadaki DK, Niyogi SK 1993 The functional importance of hydrophobicity of the tyrosine at position 13 of human epidermal growth factor in receptor binding. J Biol Chem 268: 10114–10119PubMedGoogle Scholar
  20. 21.
    Carpenter G, Cohen S 1979 Epidermal growth factor. Ann Rev Biochem 48: 193–216PubMedCrossRefGoogle Scholar
  21. 22.
    Reddy CC, Niyogi SK, Wells A, Wiley HS, Lauffenburger DA 1996 Re-engineering epidermal growth factor for enhanced potency. Nature Biotechnol 14: 1696–1699CrossRefGoogle Scholar
  22. 23.
    Bosenberg MW, Pandiella A, Massague J 1992 The cytoplasmic carboxy terminal amino acid specifies cleavage of membrane TGFa into soluble growth factor. Cell 71: 1157–1165PubMedCrossRefGoogle Scholar
  23. 24.
    Wells A 2000 Tumor invasion: role of growth factor-induced cell motility. Advances in Cancer Res 78: 31–101CrossRefGoogle Scholar
  24. 25.
    Wells A 2000 The epidermal growth factor receptor — a new target in cancer therapy. Signal 1: 4–10Google Scholar
  25. 26.
    Shoyab M, Plowman GD, McDonald VI, Bradley JG, Todaro GJ 1989 Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science 243: 1074–1076PubMedCrossRefGoogle Scholar
  26. 27.
    Higashiyama S, Abraham JA, Klagsbrun M 1993 Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate. J Cell Biol 122: 933–940PubMedCrossRefGoogle Scholar
  27. 28.
    Murphy-Ullrich J 1995 Anti-adhesive proteins of the extracellular matrix: thrombospondin, tenascin, and SPARC. Trends Glycosci Glyc 7: 89–100CrossRefGoogle Scholar
  28. 29.
    Wells A, Gupta K, Chang P, Swindle S, Glading A, Shiraha H 1998 Epidermal growth factor receptor-mediated motility in fibroblasts. Microscopy Res Techniq 43: 395–411CrossRefGoogle Scholar
  29. 30.
    Weber W, Bertics PJ, Gill GN 1984 Immunoaffinity purification of the epidermal growth factor receptor: stoichiometry of binding and kinetics of self-phosphorylation. J Biol Chem 259: 14631–14636PubMedGoogle Scholar
  30. 31.
    Qian X, LeVea CM, Freeman JK, Dougall WC, Greene MI 1994 Heterodimerization of epidermal growth factor receptor and wild-type or kinase-deficient Neu: a mechanism of interreceptor kinase activation and transphosphorylation. Proc Natl Acad Sci (USA) 91: 1500–1504CrossRefGoogle Scholar
  31. 32.
    Hill K, Welti S, Yu J, Murray JT, Yip S-C, Condeelis JS, Segall JE, Backers JM 2000 Specific requirement for the p85-p110a phosphatidylinositol 3-kinase during epidermal growth factor-stimulated actin nucleation in breast cancer cells. J Biol Chem 275: 3741–3744PubMedCrossRefGoogle Scholar
  32. 33.
    Glading A, Chang P, Lauffenburger DA, Wells A 2000 Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERIC/MAP kinase signaling pathway. J Biol Chem 275: 2390–2398PubMedCrossRefGoogle Scholar
  33. 34.
    Xie H, Pallero MA, Gupta D, Chang P, Ware MF, Witke W, Kwiatkowski DJ, Lauffenburger DA, Murphy-Ullrich JE, Wells A 1998 EGF receptor regulation of cell motility: EGF induces disassembly of focal adhesions independently of the motility-associated PLCy signaling pathway. J Cell Sci 111: 615–624PubMedGoogle Scholar
  34. 35.
    Assoian R 1997 Anchorage-dependent cell cycle progression. J Cell Biol 136: 1–4PubMedCrossRefGoogle Scholar
  35. 36.
    Segall JE, Tyerech S, Boselli L, Masseling S, Helft J, Chan A, Jones J, Condeelis J 1996 EGF stimulates lamellipod extension in metastatic mammary adenocarcinoma cells by an actin-dependent mechanism. Clin Exp Metastas 14: 61–72CrossRefGoogle Scholar
  36. 37.
    Hall A 1998 Rho GTPases and the actin cytoskeleton. Science 279: 509–514PubMedCrossRefGoogle Scholar
  37. 38.
    Ji Q-S, Ermini S, Baulida J, Sun F-L, Carpenter G 1998 Epidermal growth factor signaling and mitogenesis in Plcgl null mouse embryonic fibroblasts. Mol Biol Cell 9: 749–757PubMedGoogle Scholar
  38. 39.
    Kundra V, Escobedo JA, Kazlauskas A, Kim HK, Rhee SG, Williams LT, Zetter BR 1994 Regulation of chemotaxis by the platelet-derived growth factor receptor-ß. Nature 367: 474–476PubMedCrossRefGoogle Scholar
  39. 40.
    Derman MP, Chen JY, Spokes KC, Songyang Z, Cantley LG 1996 An 11-amino acid sequence from c-met initiates epithelial chemotaxis via phosphatidylinositol 3-kinase and phospholipase C. J Biol Chem 271: 4251–4255PubMedCrossRefGoogle Scholar
  40. 41.
    Bornfeldt ICE, Raines EW, Nakano T, Graves LM, Krebs EG, Ross R 1994 Insulin-like growth factor-1 and platelet-derived growth factor-BB induce directed migration of human arterial smooth muscle cells via signalling pathways that are distinct from those of proliferation. J Clin Invest 93: 1266–1274PubMedCrossRefGoogle Scholar
  41. 42.
    Polk DB 1998 Epidermal growth factor receptor-stimulated intestinal epithelial cell migration requires phospholipase C activity. Gastroenterology 114: 493–502PubMedCrossRefGoogle Scholar
  42. 43.
    Xie H, Turner T, Wang M-H, Singh RK, Siegal GP, Wells A 1995 In vitro invasiveness of DU-145 human prostate carcinoma cells is modulated by EGF receptor-mediated signals. Clin Exp Metastas 13: 407–419CrossRefGoogle Scholar
  43. 44.
    Kassis J, Moellinger J, Lo H, Greenberg N, Kim H-G, Wells A 1999 A role for phospholipase C-y-mediated signaling in tumor cell invasion. Clin Cancer Res 5: 2251–2260PubMedGoogle Scholar
  44. 45.
    Sa G, Fox PL 1994 Basic fibroblast growth factor-stimulated endothelial cell movement is mediated by a pertussis-sensitive pathway regulating phospholipase A2 activity. J Biol Chem 269: 3219–3225PubMedGoogle Scholar
  45. 46.
    Clyman RI, Peters KG, Chen YQ, Escobedo J, Williams LT, Ives HE, Wilson E 1994 Phospholipase C-y activation, phosphotidylinositol hydrolysis, and calcium mobilization are not required for FGF receptor-mediated chemotaxis. Cell Adhes Commun 1: 333–342PubMedCrossRefGoogle Scholar
  46. 47.
    Cation V, Romanelli RG, Pinzani M, Laffi G, Gentilini P 1997 Focal adhesion kinase and phospholipase Cy involvement in adhesion and migration of human hepatic stellate cells. Gastroenterology 112: 522–531CrossRefGoogle Scholar
  47. 48.
    Hsuan JJ, Tan SH 1997 Growth factor-dependent phosphoinositide signalling. Int J Biochem Cell Biol 29: 415–435PubMedCrossRefGoogle Scholar
  48. 49.
    Kauffmann-Zeh A, Thomas GM, Ball A, Prosser S, Cunningham E, Cockcroft S, Hsuan JJ 1995 Requirement for phosphatidylinositol transfer protein in epidermal growth factor signaling. Science 268: 1188–1190PubMedCrossRefGoogle Scholar
  49. 50.
    Yauch RL, Berdichevski F, Harler MB, Reichner J, Hemler ME 1998 Highly stoichiometric, stable, and specific association of integrin α3131 with CD151 provides a major link to phosphatidylinositol 4-kinase, and may regulate cell migration. Mol Biol Cell 9: 2751–2765PubMedGoogle Scholar
  50. 51.
    Janmey PA, Lamb J, Allen PG, Matsudaira PT 1992 Phosphoinositide-binding peptides derived from the sequences of gelsolin and villin. J Biol Chem 267: 11818–11823PubMedGoogle Scholar
  51. 52.
    Goldschmidt-Clermont PJ, Mechesky LM, Baldassare JJ, Pollard TD 1990 The actin-binding protein profilin binds to PIP2 and inhibits its hydrolysis by PLC. Science 247: 1575–1578PubMedCrossRefGoogle Scholar
  52. 53.
    Onoda K, Yu FX, Yin HL 1993 gCap39 is a nuclear and cyotplasmic protein. Cell Motil Cytoskel 26: 227–238Google Scholar
  53. 54.
    Lamb JA, Allen PG, Tuan BY, Janmey PA 1993 Modulation of gelsolin function: activation at low pH overrides Ca2+ requirement. J Biol Chem 268: 8999–9004PubMedGoogle Scholar
  54. 55.
    Weeds A, Maciver S 1993 F-actin capping proteins. Curt Opin Cell Biol 5: 63–9CrossRefGoogle Scholar
  55. 56.
    Chen P, Murphy-Ullrich J, Wells A 1996 A role for gelsolin in actuating EGF receptor-mediated cell motility. J Cell Biol 134: 689–698PubMedCrossRefGoogle Scholar
  56. 57.
    Theriot JA, Mitchison TJ 1993 The three faces of profilin. Cell 75: 835–838PubMedCrossRefGoogle Scholar
  57. 58.
    Fukami K, Furuhashi K, Inagaki M, Endo T, Hatano S, Takenawa T 1992 Requirement of phosphatidylinositol 4,5-bisphosphate for a-actinin function. Nature 359: 150–152PubMedCrossRefGoogle Scholar
  58. 59.
    Gilmore AP, Burridge K 1996 Regulation of vinculin binding to talin and actin by phosphatidyl-inositol-4–5-bisphoshate. Nature 381: 531–535PubMedCrossRefGoogle Scholar
  59. 60.
    Niggli V, Andreoli C, Roy C, Mangeat P 1995 Identification of a phosphatidylinositol4,5-bisphosphate-binding domain in the N-terminal region of ezrin. FEBS Lett 376: 172176Google Scholar
  60. 61.
    Honda K, Yamada T, Endo R, Ino Y, Gotoh M, Tsuda H, Yamada Y, Chiba H, Ijirohashi S 1998 Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion. J Cell Biol 140: 1383–1393PubMedCrossRefGoogle Scholar
  61. 62.
    Wells A, Ware MF, Allen FD, Lauffenburger DA 1999 Shaping up for shipping out: PLCy signaling of morphology changes in EGF-stimulated fibroblast migration. Cell Motil Cytoskel 44: 227–233CrossRefGoogle Scholar
  62. 63.
    Welsh JB, Gill GN, Rosenfeld MG, Wells A 1991 A negative feedback loop attenuates EGF-induced morphological changes. J Cell Biol 114: 533–543PubMedCrossRefGoogle Scholar
  63. 64.
    Chen P, Xie H, Wells A 1996 Mitogenic signaling from the EGF receptor is attenuated by a motility-associated phospholipase C-y/protein kinase C feedback mechanism. Mol Biol Cell 7: 871–881PubMedGoogle Scholar
  64. 65.
    Davis RJ, Czech MP 1987 Stimulation of epidermal growth factor receptor threonine 654 phosphorylation by platelet-derived growth factor in protein kinase C-deficient human fibroblasts. J Biol Chem 262: 6832–6841PubMedGoogle Scholar
  65. 66.
    Manos EJ, Kim M, Kassis J, Chang B, Wells A, Jones DA 2001 Prostin-1, a novel phospholipase C-y regulated gene negatively associated with prostate tumor invasion. Oncogene 20: 2781–2790PubMedCrossRefGoogle Scholar
  66. 67.
    Davis RJ 1993 The mitogen-activated protein kinase signal transduction pathway. J Biol Chem 268: 14553–14556PubMedGoogle Scholar
  67. 68.
    Sasaoka T, Langlois WJ, Bai F, Rose DW, Leitner JW, Decker SJ, Saltiel AR, Gill GN, Kobayashi M, Draznin B, Olefsky JM 1996 Involvement of ErbB2 in the signaling pathway leading to cell cycle progression from a truncated epidermal growth factor receptor lacking the C-terminal autophosphorylation sites. J Biol Chem 271: 8338–8344PubMedCrossRefGoogle Scholar
  68. 69.
    Hochholdinger F, Baier G, Nogalo A, Bauer B, Grunicke HH, Uberall F 1999 Novel membrane-targeted erk1 and erk2 chimeras which act as dominant negative, isotypespecific mitogen-activated protein kinase inhibitors of ras-raf-mediated transcriptional activation of c-fos in NIH 3T3 cells. Mol Cell Biol 19: 8052–8065PubMedGoogle Scholar
  69. 70.
    Groom LA, Sneddon AA, Alessi DR, Dowd S, Keyse SM 1996 Differential regulation of the MAP, SAP and RK/p38 kinases by Pystl, a novel cytosolic dual-specificity phosphatase. EMBO J 15: 3621–3632PubMedGoogle Scholar
  70. 71.
    Pages G, Lenormand P, L’Allemain G, Chambard J-C, Meloche S, Pouyssegur J 1993 Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci (USA) 90: 8319–8323CrossRefGoogle Scholar
  71. 72.
    Walker F, Kato A, Gonez LJ, Hibbs ML, Pouliot N, Levitzki A, Burgess AW 1998 Activation of the ras/mitogen-activated protein kinase pathway by kinase-defective epidermal growth factor receptors results in cell survival but not proliferation. Mol Cell Biol 18: 7192–7204PubMedGoogle Scholar
  72. 73.
    Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee J-D 1998 Bmkl/erk5 is required for cell proliferation induced by epidermal growth factor. Nature 395: 713–716PubMedCrossRefGoogle Scholar
  73. 74.
    English JM, Pearson G, Hockenberry T, Shivakumar L, White MA, Cobb MB 1999 Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control. J Biol Chem 274: 26563–26571CrossRefGoogle Scholar
  74. 75.
    Klemke RL, Cai S, Giannini AL, Gallagher PJ, deLanerolle P, Cheresh DA 1997 Regulation of cell motility by mitogen-activated protein kinase. J Cell Biol 137: 481–492PubMedCrossRefGoogle Scholar
  75. 76.
    Murthy KS, Grider JR, Kuemmerle JF, Makhlouf GM 2000 Sustained muscle contraction induced by agonists, growth factors, and Ca(2+) mediated by distinct PKC isozymes. Am J Physiol 279: G201–210Google Scholar
  76. 77.
    Morrison P, Takishima K, Rosner MR 1993 Role of threonine residues in regulation of the epidermal growth factor receptor by protein kinase C and mitogen-activated protein kinase. J Biol Chem 268: 15536–15543PubMedGoogle Scholar
  77. 78.
    Haugh JM, Huang AC, Wiley HS, Wells A, Lauffenburger DA 1999 Participation of internalized epidermal growth factor receptors in the activation of p2lras. J Biol Chem 274: 34350–34360PubMedCrossRefGoogle Scholar
  78. 79.
    Zhong Z, Wen Z, Darnell JE 1994 Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264: 95–99PubMedCrossRefGoogle Scholar
  79. 80.
    David M, Wong L, Flavell R, Thompson SA, Wells A, Lamer AC, Johnson GR 1996 STAT activation by epidermal growth factor (EGF) and amphiregulin: requirement for the EGF receptor kinase but not for tyrosine phosphorylation sites or JAK1. J Biol Chem 271: 9185–9188PubMedCrossRefGoogle Scholar
  80. 81.
    Williams JG 2000 STAT signalling in cell proliferation and development. Curr Opin Gen Dev 10: 503–507CrossRefGoogle Scholar
  81. 82.
    Grandis JR, Drenuing SD, Chakraborty A, Zhou M-Y, Zeng Q, Pitt AS, Tweardy DJ 1998 Requirement of Stat3 but not Statl activation for epidermal growth factor receptor-mediated cell growth in vitro. J Clin Invest 102: 1385–1392PubMedCrossRefGoogle Scholar
  82. 83.
    Song JI, Grandis JR 2000 STAT signaling in head and neck cancer. Oncogene 19: 2489–2495PubMedCrossRefGoogle Scholar
  83. 84.
    Chen P, Gupta K, Wells A 1994 Cell movement elicited by epidermal growth factor receptor requires kinase and autophosphorylation but is separable from mitogenesis. J Cell Biol 124: 547–555PubMedCrossRefGoogle Scholar
  84. 85.
    Malliri A, Symons M, Hennigan RF, Hurlstone AFL, Lamb RF, Wheeler T, Ozanne BW 1998 The transcriptional factor AP-1 is required for EGF-induced activation of rho-like GTPases, cytoskeletal rearrangements, motility, and in vitro invasion of A431 cells. J Cell Biol 143: 1087–1099PubMedCrossRefGoogle Scholar
  85. 86.
    Kustikova O, Kramerov D, Grigorian M, Berezin V, Bock E, Lukanidin E, Tulchinsky E 1998 Fra-1 induces morphological transformation and increases in vitro invasiveness and motility of epithelioid adenocarcinoma cells. Mol Cell Biol 18: 7095–7105PubMedGoogle Scholar
  86. 87.
    Cybulsky AV, McTavish AJ, Cyr MD 1994 Extracellular matrix modulates epidermal growth factor receptor activation in rat glomerular epithelial cells. J Clin Invest 94: 68–78PubMedCrossRefGoogle Scholar
  87. 88.
    Bornfeldt KE, Raines EW, Graves LM, Skinner MP, Krebs EG, Ross R 1995 Platelet-derived growth factor. Distinct signal transduction pathways associated with migration versus proliferation. Ann NY Acad Sci 766: 416–430PubMedCrossRefGoogle Scholar
  88. 89.
    Alford D, Baeckstrom D, Geyp M, Pitha P, Taylor-Papadimitriou P 1998 Integrinmatrix interactions affect the form of the structures developing from human mammary epithelial cells in collagen or fibrin gels. J Cell Sci 111: 521–532PubMedGoogle Scholar
  89. 90.
    Lin Y-C, Grinnell F 1993 Decreased level of PDGF-stimulated receptor autophosphorylation by fibroblasts in mechanically relaxed collagen matrices. J Cell Biol 122: 663–672PubMedCrossRefGoogle Scholar
  90. 91.
    Xu J, Clark RAF 1996 Extracellular matrix alters PDGF regulation of fibroblast integrins. J Cell Biol 132: 239–249PubMedCrossRefGoogle Scholar
  91. 92.
    Xu J, Zutter MM, Santoro SA, Clark RAF 1998 A three-dimensional collagen lattice activates NF-kB in human fibroblasts: role in integrin az gene expression and tissue remodeling. J Cell Biol 140: 709–719PubMedCrossRefGoogle Scholar
  92. 93.
    Zhu X, Ohtsubo M, Bohmer RM, Roberts JM, Assoian RK 1996 Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol 133: 391–403PubMedCrossRefGoogle Scholar
  93. 94.
    Bohmer R-M, Scharf E, Assoian RK 1996 Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin Dl. Mol Biol Cell 7: 101–111PubMedGoogle Scholar
  94. 95.
    Roovers K, Davey G, Zhu X, Bottazzi ME, Assoian RK 1999 α5131 integrin controls cyclin DI expression by sustaining mitogen-activated protein kinase activity in growth factor-treated cells. Mol Biol Cell 10: 3197–3204Google Scholar
  95. 96.
    Miyamoto S, Teramoto H, Gutkind JS, Yamada KM 1996 Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J Cell Biol 135: 1633–1642PubMedCrossRefGoogle Scholar
  96. 97.
    Huttenlocher A, Palecek SP, Lu Q, Zhang W, Mellgren RL, Lauffenburger DA, Ginsburg MH, Horwitz AF 1997 Regulation of cell migration by the calcium-dependent protease calpain. J Biol Chem 272: 32719–32722PubMedCrossRefGoogle Scholar
  97. 98.
    Lee J, Ishihara A, Oxford G, Johnson B, Jacobson K 1999 Regulation of cell movement is mediated by stretch-activated calcium channels. Nature 400: 382–386PubMedCrossRefGoogle Scholar
  98. 99.
    Chen JD, Kim JP, Zhang K, Sarret Y, Wynn KC, Kramer RH, Woodley DT 1993 Epidermal growth factor (EGF) promotes human keratinocyte locomotion on collagen by increasing the alpha 2 integrin subunit. Exp Cell Res 209: 216–223PubMedCrossRefGoogle Scholar
  99. 100.
    Ye J, Xu RH, Taylor-Papadimitriou J, Pitha PM 1996 Sp1 binding plays a critical role in erb-B2- and v-ras-mediated downregulation of a2-integrin expression in human mammary epithelial cells. Mol Cell Biol 16: 6178–6189PubMedGoogle Scholar
  100. 101.
    Zhang M, Singh RK, Wang M-H, Wells A, Siegal GP 1996 Epidermal growth factor modulates cell attachment to hyaluronic acid by the cell surface glycoprotein CD44. Clin Exp Metastas 14: 268–276Google Scholar
  101. 102.
    Zhang M, Wang M-H, Singh RK, Wells A, Siegal GP 1997 Epidermal growth factor induces CD44 expression through a novel regulatory element in mouse fibroblasts. J Biol Chem 272: 14139–14146PubMedCrossRefGoogle Scholar
  102. 103.
    Shiraha H, Gupta K, Glading A, Wells A 1999 Chemokine transmodulation of EGF receptor signaling: IP-10 inhibits motility by decreasing EGF-induced calpain activity. J Cell Biol 146: 243–253PubMedGoogle Scholar
  103. 104.
    Carpenter G 1999 Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways. J Cell Biol 145: 697–702CrossRefGoogle Scholar
  104. 105.
    Daub H, Weiss TU, Wallasch C, Ullrich A 1996 Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379: 557–560PubMedCrossRefGoogle Scholar
  105. 106.
    Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, Ullrich A 1999 EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402: 884–888PubMedGoogle Scholar
  106. 107.
    Li J, Lin ML, Wiepz GJ, Guadarrama AG, Bertics PJ 1999 Integrin-mediated migration of murine B82L fibroblasts is dependent on the expression of an intact epidermal growth factor receptor. J Biol Chem 274: 11209–11219PubMedCrossRefGoogle Scholar
  107. 108.
    Li J, Kim Y-N, Bertics PJ 2000 Platelet-derived growth factor-stimulated migration of murine fibroblasts is associated with epidermal growth factor receptor expression and tyrosine phosphorylation. J Biol Chem 275: 2951–2958PubMedCrossRefGoogle Scholar
  108. 109.
    Adamson ED 1990 EGF receptor activities in mammalian development. Mol Reprod Dev 27: 16–22PubMedCrossRefGoogle Scholar
  109. 110.
    Miettinen PJ, Berger JE, Meneses J, Phung Y, Pedersen RA, Werb Z, Derynck R 1995 Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376: 337–341PubMedCrossRefGoogle Scholar
  110. 111.
    Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC, Barnard JA, Yuspa SH, Coffey RJ, Magnuson T 1995 Targeted disruption of mouse EGF receptor: effects of genetic background on mutant phenotype. Science 269: 230–234PubMedCrossRefGoogle Scholar
  111. 112.
    Sibilia M, Wagner EF 1995 Strain dependent epithelial defects in mice lacking the EGF receptor. Science 269: 234–238PubMedCrossRefGoogle Scholar
  112. 113.
    Xie W, Paterson AJ, Chin E, Nabell LM, Kudlow JE 1998 Targeted expression of a dominant negative epidermal growth factor receptor in the mammary gland of transgenic mice inhibits pubertal mammary duct development. Mol Endocrinol 11: 1766–1781CrossRefGoogle Scholar
  113. 114.
    Okamoto S, Oka T 1984 Evidence for physiological function of epidermal growth factor: pregestational sialoadenectomy of mice decreases milk production and increases offspring mortality during lactation period. Proc Natl Acad Sci (USA) 81: 6059–6063CrossRefGoogle Scholar
  114. 115.
    Downward J, Yarden Y, Mayes ELV, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield MD 1984 Close similarity of the epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307: 521–527PubMedCrossRefGoogle Scholar
  115. 116.
    Aaronson SA 1991 Growth factors and cancer. Science 254: 1146–1153PubMedCrossRefGoogle Scholar
  116. 117.
    Kim H, Turner T, Kassis J, Souto J, Wells A 1999 EGF receptor signaling in prostate development. Histol Histopathol 14: 1175–1182PubMedGoogle Scholar
  117. 118.
    Masui H, Wells A, Lazar CS, Rosenfeld MG, Gill GN 1991 Enhanced tumorigenesis of NR6 cells which express non-downregulating epidermal growth factor receptors. Cancer Res 51: 6170–6175PubMedGoogle Scholar
  118. 119.
    Simcha I, Geiger B, Yehuda-Levenberg S, Salomon D, Ben-Ze’ev A 1996 Suppression of tumorigenicity by plakoglobin: an augmenting effect of N-cadherin. J Cell Biol 133: 199–209PubMedCrossRefGoogle Scholar
  119. 120.
    DiFiore PP, Pierce JH, Fleming TP, Hazan R, Ullrich A, King CR, Schlessinger J, Aaronson SA 1987 Overexpression of the human EGF receptor confers an EGFdependent tranformed phenotype to NIH 3T3 cells. Cell 51: 1063–1070CrossRefGoogle Scholar
  120. 121.
    Matsui Y, Halter SA, Holt JT, Hogan BL, Coffey RJ 1990 Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice. Cell 61: 1147–1155PubMedCrossRefGoogle Scholar
  121. 122.
    Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC 1990 Overexpression of TGFa in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 61: 1121–1135PubMedCrossRefGoogle Scholar
  122. 123.
    Jhappan C, Stable C, Harkins RN, Fausto N, Smith GH, Merlino GT 1990 TGFct overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 61: 1137–1146PubMedCrossRefGoogle Scholar
  123. 124.
    Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS 1997 Epidermal growth factor receptor ( EGFR) and EGFR mutations, functions and possible role in clinical trials. Ann Oncol 8: 1197–1206PubMedCrossRefGoogle Scholar
  124. 125.
    Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J 1985 Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313: 144–147PubMedCrossRefGoogle Scholar
  125. 126.
    Neal DE, Marsh C, Bennett MK, Abel PD, Hall RR, Sainsbury JRC, Harris AL 1985 Epidermal-growth-factor receptors in human bladder cancer: comparison of invasive and superficial tumours. Lancet 1 (8425): 366–368PubMedCrossRefGoogle Scholar
  126. 127.
    Yasui W, Sumiyoshi H, Hata J, Kameda T, Ochiai A, Ito H, Tahara E 1988 Expression of epidermal growth factor receptor in human gastric and colon carcinomas. Cancer Res 48: 137–141PubMedGoogle Scholar
  127. 128.
    Kassis J, Lauffenburger DA, Turner T, Wells A 2001 Tumor invasion as dysregulated cell motility. Seminars in Cancer Biology 11: 105–117PubMedCrossRefGoogle Scholar
  128. 129.
    Khoshyomn S, Penar PL, Rossi J, Wells A, Abramson DL, Bhushan A 1999 Inhibition of PLC gamma-1 activation blocks glioma cell motility and invasion of fetal rat brain aggregates. Neurosurgery 44: 568–577PubMedCrossRefGoogle Scholar
  129. 130.
    Turner T, Chen P, Goodly LJ, Wells A 1996 EGF receptor signaling enhances in vivo invasiveness of DU-145 human prostate carcinoma cells. Clin Exp Metastas 14: 409–418CrossRefGoogle Scholar
  130. 131.
    Turner T, VanEpps-Fung M, Kassis J, Wells A 1997 Molecular inhibition of PLCy signaling abrogates DU-145 prostate tumor cell invasion. Clin Cancer Res 3: 2275–2282PubMedGoogle Scholar
  131. 132.
    Gilmore T, DeClue JE, Martin GS 1985 Protein phosphorylation at tyrosine is induced by the v-erbB gene product in vivo and in vitro. Cell 40: 609–618PubMedCrossRefGoogle Scholar
  132. 133.
    Bargmann CI, Hung MC, Weinberg RA 1986 Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell 45: 649–657PubMedCrossRefGoogle Scholar
  133. 134.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL 1987 Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182PubMedCrossRefGoogle Scholar
  134. 135.
    Drebin JA, Link VC, Weinberg RA, Greene MI 1986 Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen. Proc Natl Acad Sci (USA) 83: 9129–9133CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Alan Wells
    • 1
    • 2
  1. 1.Department of PathologyUniversity of PittsburghPittsburghUSA
  2. 2.Pathology and Laboratory ServicesPittsburgh VAMCPittsburghUSA

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