The Epidermal Growth Factor Receptor in Normal and Neoplastic Epithelia

  • Susan K. Repertinger
  • Justin G. Madson
  • Kyle J. Bichsel
  • Laura A. HansenEmail author


The epidermal growth factor receptor (EGFR) regulates a plethora of cellular and tissue functions in epithelia including cell division, survival, differentiation, and migration. EGFR signaling is up-regulated in pathologies involving aberrant growth like squamous cancer, and facilitates neoplastic progression. Many mechanisms through which the effects of EGFR are modulated in normal and pathological processes have been identified. In particular, recent research has yielded important and surprising insights into the effects of EGFR-dependent signaling on cutaneous biology and carcinogenesis. This review focuses on EGFR signaling in normal biology and squamous cancer, with emphasis on the skin as a model organ to illustrate the biological significance of EGFR signaling.


Epidermal Growth Factor Receptor Papillary Thyroid Carcinoma Epidermal Growth Factor Receptor Expression Actinic Keratosis Epidermal Growth Factor Receptor Inhibitor 
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.


  1. Abud HE, Watson N, Heath JK (2005) Growth of intestinal epithelium in organ culture is dependent on EGF signalling. Exp Cell Res 303:252–262PubMedCrossRefGoogle Scholar
  2. Andl CD, Mizushima T, Nakagawa H, Oyama K, Harada H, Chruma K, Herlyn M, Rustgi AK (2003) Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo. J Biol Chem 278:1824–1830PubMedCrossRefGoogle Scholar
  3. Andl CD, Mizushima T, Oyama K, Bowser M, Nakagawa H, Rustgi AK (2004) EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes. Am J Physiol Gastrointest Liver Physiol 287:G1227–G1237PubMedCrossRefGoogle Scholar
  4. Arcidiacono MV, Sato T, varez-Hernandez D, Yang J, Tokumoto M, Gonzalez-Suarez I, Lu Y, Tominaga Y, Cannata-Andia J, Slatopolsky Dusso AS (2008) EGFR activation increases parathyroid hyperplasia and calcitriol resistance in kidney disease. J Am Soc Nephrol 19:310–320PubMedCrossRefGoogle Scholar
  5. Bender K, Blattner C, Knebel A, Iordanov M, Herrlich P, Rahmsdorf HJ (1997) UV-induced signal transduction. J Photochem Photobiol B 37:1–17PubMedCrossRefGoogle Scholar
  6. Bhola NE, Grandis JR (2008) Crosstalk between G-protein-coupled receptors and epidermal growth factor receptor in cancer. Front Biosci 13:1857–1865PubMedCrossRefGoogle Scholar
  7. Brandt R, Eisenbrandt R, Leenders F, Zschiesche W, Binas B, Juergensen C, Theuring F (2000) Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation. Oncogene 19:2129–2137PubMedCrossRefGoogle Scholar
  8. Canguilhem B, Pradines A, Baudouin C, Boby C, Lajoie-Mazenc I, Charveron M, Favre G (2005) RhoB protects human keratinocytes from UVB-induced apoptosis through epidermal growth factor receptor signaling. J Bio chem 280:43257–43263Google Scholar
  9. Casanova ML, Larcher F, Casanova B, Murillas R, Fernandez-Acenero MJ, Villanueva C, Martinez-Palacio J, Ullrich A, Conti CJ, Jorcano JL (2002) A critical role for ras-mediated, epidermal growth factor receptor-dependent angiogenesis in mouse skin carcinogenesis 2. Cancer Res 62:3402–3407PubMedGoogle Scholar
  10. Chen P, Xie H, Sekar MC, Gupta K, Wells A (1994) Epidermal growth factor receptor-mediated cell motility: phospholipase C activity is required, but mitogen-activated protein kinase activity is not sufficient for induced cell movement. J Cell Biol 127:847–857PubMedCrossRefGoogle Scholar
  11. Chin YE, Kitagawa M, Kuida K, Flavell RA, Fu XY (1997) Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol 17:5328–5337PubMedGoogle Scholar
  12. Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174PubMedCrossRefGoogle Scholar
  13. Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505–516PubMedCrossRefGoogle Scholar
  14. Coffey RJ, Derynck R, Wilcox JN, Bringman TS, Goustin AS, Moses HL, Pittelkow MR (1987) Production and auto-induction of transforming growth factor- alpha in human keratinocytes. Nature 328:817–820PubMedCrossRefGoogle Scholar
  15. Cook PW, Mattox PA, Keeble WW, Pittelkow MR, Plowman GD, Shoyab M, Adelman JP, Shipley GD (1991) A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin. Mol Cell Biol 11:2547–2557PubMedGoogle Scholar
  16. Croyle M, Akeno N, Knauf JA, Fabbro D, Chen X, Baumgartner JE, Lane HA, Fagin JA (2008) RET/PTC-induced cell growth is mediated in part by epidermal growth factor receptor (EGFR) activation: evidence for molecular and functional interactions between RET and EGFR. Cancer Res 68:4183–4191PubMedCrossRefGoogle Scholar
  17. Dassonville O, Formento JL, Francoual M, Ramaioli A, Santini J, Schneider M, Demard F, Milano G (1993) Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J Clin Oncol 11:1873–1878PubMedGoogle Scholar
  18. Dise RS, Frey MR, Whitehead RH, Polk DB (2008) Epidermal growth factor stimulates Rac activation through Src and phosphatidylinositol 3-kinase to promote colonic epithelial cell migration. Am J Physiol Gastrointest Liver Physiol 294:G276–G285PubMedCrossRefGoogle Scholar
  19. Dlugosz AA, Hansen L, Cheng C, Alexander N, Denning MF, Threadgill DW, Magnuson T, Coffey RJ Jr, Yuspa SH (1997) Targeted disruption of the epidermal growth factor receptor impairs growth of squamous papillomas expressing the v-ras Ha oncogene but does not block in vitro keratinocyte responses to oncogenic ras. Cancer Res 57:3180–3188PubMedGoogle Scholar
  20. Donnini S, Finetti F, Solito R, Terzuoli E, Sacchetti A, Morbidelli L, Patrignani P, Ziche M (2007) EP2 prostanoid receptor promotes SCC growth through epidermal growth factor receptor transactivation and iNOS and ERK1/2 pathways. FASEB J 21:2418–2430PubMedCrossRefGoogle Scholar
  21. Duh G, Mouri N, Warburton D, Thomas DW (2000) EGF regulates early embryonic mouse gut development in chemically defined organ culture. Pediatr Res 48:794–802PubMedCrossRefGoogle Scholar
  22. Edwards DR, Handsley MM, Pennington CJ (2008) The ADAM metalloproteinases. Mol Aspects Med 29:258–289PubMedCrossRefGoogle Scholar
  23. El Abaseri TB, Fuhrman J, Trempus C, Shendrik I, Tennant RW, Hansen LA (2005) Chemoprevention of UV light-induced skin tumorigenesis by inhibition of the epidermal growth factor receptor. Cancer Res 65:3958–3965PubMedCrossRefGoogle Scholar
  24. El Abaseri TB, Putta S, Hansen LA (2006) Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor. Carcinogenesis 27:225–231PubMedCrossRefGoogle Scholar
  25. Fagin JA (2004) How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy. J Endocrinol 183:249–256PubMedCrossRefGoogle Scholar
  26. Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284:14–30PubMedCrossRefGoogle Scholar
  27. Fischer OM, Hart S, Gschwind A, Ullrich A (2003) EGFR signal transactivation in cancer cells. Biochem Soc Trans 31:1203–1208PubMedCrossRefGoogle Scholar
  28. Forsberg S, Ostman A, Rollman O (2008) Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase. Arch Dermatol Res 300:505–516PubMedCrossRefGoogle Scholar
  29. Freeman M (2004) Proteolysis within the membrane: rhomboids revealed. Nat Rev Mol Cell Biol 5:188–197PubMedCrossRefGoogle Scholar
  30. Frusic-Zlotkin M, Raichenberg D, Wang X, David M, Michel B, Milner Y (2006) Apoptotic mechanism in pemphigus autoimmunoglobulins-induced acantholysis–possible involvement of the EGF receptor. Autoimmunity 39:563–575PubMedCrossRefGoogle Scholar
  31. Fuchs E (1990) Epidermal differentiation. Curr Opin Cell Biol 2:1028–1035PubMedCrossRefGoogle Scholar
  32. Fuchs E (2008) Skin stem cells: rising to the surface. J Cell Biol 180:273–284PubMedCrossRefGoogle Scholar
  33. Getsios S, Simpson CL, Kojima S, Harmon R, Sheu LJ, Dusek RL, Cornwell M, Green KJ (2009) Desmoglein 1-dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis. J Cell Biol 185:1243–1258PubMedCrossRefGoogle Scholar
  34. Guy PM, Platko JV, Cantley LC, Cerione RA, Carraway KL III (1994) Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci USA 91:8132–8136PubMedCrossRefGoogle Scholar
  35. Hallman MA, Zhuang S, Schnellmann RG (2008) Regulation of dedifferentiation and redifferentiation in renal proximal tubular cells by the epidermal growth factor receptor. J Pharmacol Exp Ther 325:520–528PubMedCrossRefGoogle Scholar
  36. Hama T, Yuza Y, Saito Y, Uchi J, Kondo S, Okabe M, Yamada H, Kato T, Moriyama H, Kurihara S, Urashima M (2009) Prognostic significance of epidermal growth factor receptor phosphorylation and mutation in head and neck squamous cell carcinoma. Oncologist 14(9):900–908PubMedCrossRefGoogle Scholar
  37. Han CY, Lim SC, Choi HS, Kang KW (2008) Induction of ErbB2 by ultraviolet A irradiation: potential role in malignant transformation of keratinocytes. Cancer Sci 99:502–509PubMedCrossRefGoogle Scholar
  38. Hansen LA, Lichti U, Tennenbaum T, Dlugosz AA, Threadgill DW, Magnuson T, Yuspa SH (1996) Altered hair follicle morphogenesis in epidermal growth factor receptor deficient mice. In: Van Neste DJJ, Randall VA (eds) Hair research for the next millennium. Elsevier Science BV, Amsterdam, pp 425–431Google Scholar
  39. Hansen LA, Alexander N, Hogan ME, Sundberg JP, Dlugosz A, Threadgill DW, Magnuson T, Yuspa SH (1997) Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. Am J Pathol 150:1959–1975PubMedGoogle Scholar
  40. Hansen LA, Woodson RL II, Holbus S, Strain K, Lo Y-C, Yuspa SH (2000) The epidermal growth factor receptor is required to maintain the proliferative population in the basal compartment of epidermal tumors. Cancer Res 60:3328–3332PubMedGoogle Scholar
  41. Hashimoto K (2000) Regulation of keratinocyte function by growth factors. J Dermatol Sci 24 (Suppl) 1:S46–S50Google Scholar
  42. Hashimoto K, Higashiyama S, Asada H, Hashimura E, Kobayashi T, Sudo K, Nakagawa T, Damm D, Yoshikawa K, Taniguchi N (1994) Heparin-binding epidermal growth factor-like growth factor is an autocrine growth factor for human keratinocytes. J Biol Chem 269:20060–20066PubMedGoogle Scholar
  43. Huang RP, Wu JX, Fan Y, Adamson ED (1996) UV activates growth factor receptors via reactive oxygen intermediates. J Cell Biol 133:211–220PubMedCrossRefGoogle Scholar
  44. Hyatt DC, Ceresa BP (2008) Cellular localization of the activated EGFR determines its effect on cell growth in MDA-MB-468 cells. Exp Cell Res 314:3415–3425PubMedCrossRefGoogle Scholar
  45. Hynes NE, Macdonald G (2009) ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21:177–184PubMedCrossRefGoogle Scholar
  46. Jarboe MD, Juno RJ, Stehr W, Bernal NP, Profitt S, Erwin CR, Warner BW (2005) Epidermal growth factor receptor signaling regulates goblet cell production after small bowel resection. J Pediatr Surg 40:92–97PubMedCrossRefGoogle Scholar
  47. Kashiwagi M, Kuroki T, Huh N (1997) Specific inhibition of hair follicle formation by epidermal growth factor in an organ culture of developing mouse skin. Dev Biol 189:22–32PubMedCrossRefGoogle Scholar
  48. Klapper LN, Kirschbaum MH, Sela M, Yarden Y (2000) Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res 77:25–79PubMedCrossRefGoogle Scholar
  49. Knebel A, Rahmsdorf HJ, Ullrich A, Herrlich P (1996) Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J 15:5314–5325PubMedGoogle Scholar
  50. Koch S, Nusrat A (2009) Dynamic regulation of epithelial cell fate and barrier function by intercellular junctions. Ann NY Acad Sci 1165:220–227PubMedCrossRefGoogle Scholar
  51. Koivisto L, Jiang G, Hakkinen L, Chan B, Larjava H (2006) HaCaT keratinocyte migration is dependent on epidermal growth factor receptor signaling and glycogen synthase kinase-3alpha. Exp Cell Res 312:2791–2805PubMedCrossRefGoogle Scholar
  52. Kolev V, Mandinova A, Guinea-Viniegra J, Hu B, Lefort K, Lambertini C, Neel V, Dummer R, Wagner EF, Dotto GP (2008) EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer. Nat Cell Biol 10:902–911PubMedCrossRefGoogle Scholar
  53. Koster MI, Roop DR (2007) Mechanisms regulating epithelial stratification. Annu Rev Cell Dev Biol 23:93–113PubMedCrossRefGoogle Scholar
  54. Kottke TJ, Blajeski AL, Martins LM, Mesner PW Jr, Davidson NE, Earnshaw WC, Armstrong DK, Kaufmann SH (1999) Comparison of paclitaxel-, 5-fluoro-2’-deoxyuridine-, and epidermal growth factor (EGF)-induced apoptosis. Evidence for EGF-induced anoikis. J Biol Chem 274:15927–15936PubMedCrossRefGoogle Scholar
  55. Krahn G, Leiter U, Kaskel P, Udart M, Utikal J, Bezold G, Peter RU (2001) Coexpression patterns of EGFR, HER2, HER3 and HER4 in non-melanoma skin cancer. Eur J Cancer 37:251–259PubMedCrossRefGoogle Scholar
  56. Kusewitt DF, Choi C, Newkirk KM, Leroy P, Li Y, Chavez MG, Hudson LG (2009) Slug/Snai2 is a downstream mediator of epidermal growth factor receptor-stimulated reepithelialization. J Invest Dermatol 129:491–495PubMedCrossRefGoogle Scholar
  57. Lechler T, Fuchs E (2005) Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437:275–280PubMedCrossRefGoogle Scholar
  58. Lewis DA, Zweig B, Hurwitz SA, Spandau DF (2003) Inhibition of erbB receptor family members protects HaCaT keratinocytes from ultraviolet-B-induced apoptosis. J Invest Dermatol 120:483–488PubMedCrossRefGoogle Scholar
  59. Ley KD, Ellem KA (1992) UVC modulation of epidermal growth factor receptor number in HeLa S3 cells. Carcinogenesis 13:183–187PubMedCrossRefGoogle Scholar
  60. Li S, Wang Q, Wang Y, Chen X, Wang Z (2009) PLC-gamma1 and Rac1 coregulate EGF-induced cytoskeleton remodeling and cell migration. Mol Endocrinol 23:901–913PubMedCrossRefGoogle Scholar
  61. Linardou H, Dahabreh IJ, Bafaloukos D, Kosmidis P, Murray S (2009) Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nat Rev Clin Oncol 6:352–366PubMedCrossRefGoogle Scholar
  62. Liu Y, Poon RT, Shao W, Sun X, Chen H, Kok TW, Fan ST (2007) Blockage of epidermal growth factor receptor by quinazoline tyrosine kinase inhibitors suppresses growth of human hepatocellular carcinoma. Cancer Lett 248:32–40PubMedCrossRefGoogle Scholar
  63. Madson JG, Lynch DT, Tinkum KL, Putta SK, Hansen LA (2006) Erbb2 regulates inflammation and proliferation in the skin after ultraviolet irradiation. Am J Pathol 169:1402–1414PubMedCrossRefGoogle Scholar
  64. Maklad A, Nicolai JR, Bichsel KJ, Evenson JE, Lee TC, Threadgill DW, Hansen LA (2009) The EGFR Is Required for Proper Innervation to the Skin. J Invest Dermatol 129:690–698PubMedCrossRefGoogle Scholar
  65. Mariotti A, Kedeshian PA, Dans M, Curatola AM, Gagnoux-Palacios L, Giancotti FG (2001) EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J Cell Biol 155:447–458PubMedCrossRefGoogle Scholar
  66. Mascia F, Mariani V, Girolomoni G, Pastore S (2003) Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. Am J Pathol 163:303–312PubMedGoogle Scholar
  67. 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
  68. Minami S, Iwamoto R, Mekada E (2008) HB-EGF decelerates cell proliferation synergistically with TGFalpha in perinatal distal lung development. Dev Dyn 237:247–258PubMedCrossRefGoogle Scholar
  69. Modjtahedi H, Affleck K, Stubberfield C, Dean C (1998) EGFR blockade by tyrosine kinase inhibitor or monoclonal antibody inhibits growth, directs terminal differentiation and induces apoptosis in the human squamous cell carcinoma HN5. Int J Oncol 13:335–342PubMedGoogle Scholar
  70. Morris ZS, McClatchey AI (2009) Aberrant epithelial morphology and persistent epidermal growth factor receptor signaling in a mouse model of renal carcinoma. Proc Natl Acad Sci USA 106:9767–9772PubMedCrossRefGoogle Scholar
  71. Murillas R, Larcher F, Conti CJ, Santos M, Ulrich A, Jorcano JL (1995) Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure. EMBO J 14:5216–5223PubMedGoogle Scholar
  72. Nakamura Y, Sotozono C, Kinoshita S (2001) The epidermal growth factor receptor (EGFR): role in corneal wound healing and homeostasis 5. Exp Eye Res 72:511–517PubMedCrossRefGoogle Scholar
  73. Nanney LB, Stoscheck CM, King LE Jr, Underwood RA, Holbrook KA (1990) Immunolocalization of epidermal growth factor receptors in normal developing human skin. J Invest Dermatol 94:742–748PubMedCrossRefGoogle Scholar
  74. Normanno N, De LA, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De FG, Caponigro F, Salomon DS (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366:2–16PubMedCrossRefGoogle Scholar
  75. Ohtsu H, Dempsey PJ, Eguchi S (2006) ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am J Physiol Cell Physiol 291:C1–C10PubMedCrossRefGoogle Scholar
  76. Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE (1999) ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases. J Biol Chem 274:17209–17218PubMedCrossRefGoogle Scholar
  77. Oliveira S, van Bergen en Henegouwen PM, Storm G, Schiffelers RM (2006) Molecular biology of epidermal growth factor receptor inhibition for cancer therapy. Expert Opin Biol Ther 6:605–617PubMedCrossRefGoogle Scholar
  78. Pastore S, Mascia F, Mariani V, Girolomoni G (2008) The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol 128:1365–1374PubMedCrossRefGoogle Scholar
  79. Pedersen MW, Meltorn M, Damstrup L, Poulsen HS (2001) The type III epidermal growth factor receptor mutation. Biological significance and potential target for anti-cancer therapy. Ann Oncol 12:745–760PubMedCrossRefGoogle Scholar
  80. Piepkorn M, Predd H, Underwood R, Cook P (2003) Proliferation-differentiation relationships in the expression of heparin-binding epidermal growth factor-related factors and erbB receptors by normal and psoriatic human keratinocytes. Arch Dermatol Res 295:93–101PubMedCrossRefGoogle Scholar
  81. Powell TJ, Ben-Bassat H, Klein BY, Chen H, Shenoy N, McCollough J, Narog B, Gazit A, Harzstark Z, Chaouat M, Levitzki R, Tang C, McMahon J, Shawver L, Levitzki A (1999) Growth inhibition of psoriatic keratinocytes by quinazoline tyrosine kinase inhibitors. Br J Dermatol 141:802–810PubMedCrossRefGoogle Scholar
  82. Radtke F, Raj K (2003) The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3:756–767PubMedCrossRefGoogle Scholar
  83. Ren Z., Schaefer T.S. (2002). Erbs-s activates Stat3 alpha in a Src- and JAK2 dependent manner. J. Biol. Chem. 277:38486–38493Google Scholar
  84. Repertinger SK, Campagnaro E, Fuhrman J, El Abaseri T, Yuspa SH, Hansen LA (2004) EGFR enhances early healing after cutaneous incisional wounding. J Invest Dermatol 123:982–989PubMedCrossRefGoogle Scholar
  85. Richardson GD, Bazzi H, Fantauzzo KA, Waters JM, Crawford H, Hynd P, Christiano AM, Jahoda CA (2009) KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin. Development 136:2153–2164PubMedCrossRefGoogle Scholar
  86. Rogers SJ, Harrington KJ, Rhys-Evans P, Charoenrat P, Eccles SA (2005) Biological significance of c-erbB family oncogenes in head and neck cancer. Cancer Metastasis Rev 24:47–69PubMedCrossRefGoogle Scholar
  87. Sahin U, Weskamp G, Kelly K, Zhou HM, Higashiyama S, Peschon J, Hartmann D, Saftig P, Blobel CP (2004) Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol 164:769–779PubMedCrossRefGoogle Scholar
  88. Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225PubMedCrossRefGoogle Scholar
  89. Schmidt E, Waschke J (2009) Apoptosis in pemphigus. Autoimmun Rev 8:533–537PubMedCrossRefGoogle Scholar
  90. Sheng G, Bernabe KQ, Guo J, Warner BW (2006) Epidermal growth factor receptor-mediated proliferation of enterocytes requires p21waf1/cip1 expression. Gastroenterology 131:153–164PubMedCrossRefGoogle Scholar
  91. Sheu JJ, Hua CH, Wan L, Lin YJ, Lai MT, Tseng HC, Jinawath N, Tsai MH, Chang NW, Lin CF, Lin CC, Hsieh LJ, Wang TL, Shih I, Tsai FJ (2009) Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma. Cancer Res 69:2568–2576PubMedCrossRefGoogle Scholar
  92. Shilo BZ (2005) Regulating the dynamics of EGF receptor signaling in space and time. Development 132:4017–4027PubMedCrossRefGoogle Scholar
  93. Shirakata Y, Komurasaki T, Toyoda H, Hanakawa Y, Yamasaki K, Tokumaru S, Sayama K, Hashimoto K (2000) Epiregulin, a novel member of the epidermal growth factor family, is an autocrine growth factor in normal human keratinocytes. J Biol Chem 275:5748–5753PubMedCrossRefGoogle Scholar
  94. Sibilia M, Fleischmann A, Behrens A, Stingl L, Carroll J, Watt FM, Schlessinger J, Wagner EF (2000) The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development. Cell 102:211–220PubMedCrossRefGoogle Scholar
  95. Sibilia M, Wagner EF (1995) Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269:234–238PubMedCrossRefGoogle Scholar
  96. Singer AJ, Clark RA (1999) Cutaneous wound healing4. N Engl J Med 341:738–746PubMedCrossRefGoogle Scholar
  97. Singh B, Schneider M, Knyazev P, Ullrich A (2009) UV-induced EGFR signal transactivation is dependent on proligand shedding by activated metalloproteases in skin cancer cell lines. Int J Cancer 124:531–539PubMedCrossRefGoogle Scholar
  98. Stoll SW, Johnson JL, Bhasin A, Johnston A, Gudjonsson JE, Rittie L, Elder JT (2009) Metalloproteinase-mediated, context-dependent function of amphiregulin and HB-EGF in human keratinocytes and skin. J Invest Dermatol 52:442–448Google Scholar
  99. Stoll SW, Kansra S, Peshick S, Fry DW, Leopold WR, Wiesen JF, Sibilia M, Zhang T, Werb Z, Derynck R, Wagner EF, Elder JT (2001) Differential utilization and localization of ErbB receptor tyrosine kinases in skin compared to normal and malignant keratinocytes. Neoplasia 3:339–350PubMedCrossRefGoogle Scholar
  100. Strachan L, Murison JG, Prestidge RL, Sleeman MA, Watson JD, Kumble KD (2001) Cloning and biological activity of epigen, a novel member of the epidermal growth factor superfamily. J Biol Chem 276:18265–18271PubMedCrossRefGoogle Scholar
  101. Sundaram MV (2005) The love-hate relationship between Ras and Notch. Genes Dev 19:1825–1839PubMedCrossRefGoogle Scholar
  102. Swindle CS, Tran KT, Johnson TD, Banerjee P, Mayes AM, Griffith L, Wells A (2001) Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. J Cell Biol 154:459–468PubMedCrossRefGoogle Scholar
  103. Takamune Y, Ikebe T, Nagano O, Nakayama H, Ota K, Obayashi T, Saya H, Shinohara M (2007) ADAM-17 associated with CD44 cleavage and metastasis in oral squamous cell carcinoma. Virchows Arch 450:169–177PubMedCrossRefGoogle Scholar
  104. 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: effect of genetic background on mutant phenotype. Science 269:230–234PubMedCrossRefGoogle Scholar
  105. Tzahar E, Moyer JD, Waterman H, Barbacci EG, Bao J, Levkowitz G, Shelly M, Strano S, Pinkas-Kramarski R, Pierce JH, Andrews GC, Yarden Y (1998) Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network. EMBO J 17:5948–5963PubMedCrossRefGoogle Scholar
  106. Varani J, Kang S, Stoll S, Elder JT (1998) Human psoriatic skin in organ culture: comparison with normal skin exposed to exogenous growth factors and effects of an antibody to the EGF receptor. Pathobiology 66:253–259PubMedCrossRefGoogle Scholar
  107. Vincent A, Van SI (2009) Epigenetics, stem cells and epithelial cell fate. Differentiation 78(2–3):99–107PubMedCrossRefGoogle Scholar
  108. Visco V, Belleudi F, Marchese C, Leone L, Aimati L, Cardinali G, Kovacs D, Frati L, Torrisi MR (2004) Differential response to keratinocyte growth factor receptor and epidermal growth factor receptor ligands of proliferating and differentiating intestinal epithelial cells. J Cell Physiol 200:31–44PubMedCrossRefGoogle Scholar
  109. Wan YS, Wang ZQ, Shao Y, Voorhees JJ, Fisher GJ (2001) Ultraviolet irradiation activates PI 3-kinase/AKT survival pathway via EGF receptors in human skin in vivo. Int J Oncol 18:461–466PubMedGoogle Scholar
  110. Watanabe T, Shintani A, Nakata M, Shing Y, Folkman J, Igarashi K, Sasada R (1994) Recombinant human betacellulin. Molecular structure, biological activities, and receptor interaction. J Biol Chem 269:9966–9973PubMedGoogle Scholar
  111. Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, Osborne BA, Gottipati S, Aster JC, Hahn WC, Rudolf M, Siziopikou K, Kast WM, Miele L (2002) Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 8:979–986PubMedCrossRefGoogle Scholar
  112. Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines1. Physiol Rev 83:835–870PubMedGoogle Scholar
  113. Woodworth CD, Michael E, Marker D, Allen S, Smith L, Nees M (2005) Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment. Mol Cancer Ther 4:650–658PubMedCrossRefGoogle Scholar
  114. Xie H, Pallero MA, Gupta K, 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 PLCgamma signaling pathway. J Cell Sci 111(Pt 5):615–624PubMedGoogle Scholar
  115. Xu Y, Shao Y, Voorhees JJ, Fisher GJ (2006) Oxidative inhibition of receptor-type protein-tyrosine phosphatase kappa by ultraviolet irradiation activates epidermal growth factor receptor in human keratinocytes. J Biol Chem 281:27389–27397PubMedCrossRefGoogle Scholar
  116. Yang Z, Bagheri-Yarmand R, Wang RA, Adam L, Papadimitrakopoulou VV, Clayman GL, El-Naggar A, Lotan R, Barnes CJ, Hong WK, Kumar R (2004) The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses c-Src and Pak1 pathways and invasiveness of human cancer cells. Clin Cancer Res 10:658–667PubMedCrossRefGoogle Scholar
  117. Yarden Y, Shilo BZ (2007) SnapShot: EGFR signaling pathway. Cell 131:1018PubMedCrossRefGoogle Scholar
  118. Yasmeen A, Bismar TA, Al Moustafa AE (2006) ErbB receptors and epithelial-cadherin-catenin complex in human carcinomas. Future Oncol 2:765–781PubMedCrossRefGoogle Scholar
  119. Yoshida A, Kanno H, Watabe D, Akasaka T, Sawai T (2008) The role of heparin-binding EGF-like growth factor and amphiregulin in the epidermal proliferation of psoriasis in cooperation with TNFalpha. Arch Dermatol Res 300:37–45PubMedCrossRefGoogle Scholar
  120. Zahorowska B, Crowe PJ, Yang JL (2009) Combined therapies for cancer: a review of EGFR-targeted monotherapy and combination treatment with other drugs. J Cancer Res Clin Oncol 135:1137–1148PubMedCrossRefGoogle Scholar
  121. Zorzou MP, Stratigos A, Efstathiou E, Bamias A (2004) Exacerbation of psoriasis after treatment with an EGFR tyrosine kinase inhibitor. Acta Derm Venereol 84:308–309PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Susan K. Repertinger
  • Justin G. Madson
  • Kyle J. Bichsel
  • Laura A. Hansen
    • 1
    Email author
  1. 1.Department of Biomedical SciencesCreighton University School of MedicineOmahaUSA

Personalised recommendations