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The Epidermal Growth Factor Receptor in Normal and Neoplastic Epithelia

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Signaling Pathways in Squamous Cancer

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Abstract

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.

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References

  • Abud HE, Watson N, Heath JK (2005) Growth of intestinal epithelium in organ culture is dependent on EGF signalling. Exp Cell Res 303:252–262

    Article  CAS  PubMed  Google Scholar 

  • 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 278:1824–1830

    Article  CAS  PubMed  Google Scholar 

  • 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–G1237

    Article  CAS  PubMed  Google Scholar 

  • 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 19:310–320

    Article  CAS  PubMed  Google Scholar 

  • Bender K, Blattner C, Knebel A, Iordanov M, Herrlich P, Rahmsdorf HJ (1997) UV-induced signal transduction. J Photochem Photobiol B 37:1–17

    Article  CAS  PubMed  Google Scholar 

  • Bhola NE, Grandis JR (2008) Crosstalk between G-protein-coupled receptors and epidermal growth factor receptor in cancer. Front Biosci 13:1857–1865

    Article  CAS  PubMed  Google Scholar 

  • 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 19:2129–2137

    Article  CAS  PubMed  Google Scholar 

  • 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 280:43257–43263

    CAS  Google Scholar 

  • 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 62:3402–3407

    CAS  PubMed  Google Scholar 

  • 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 127:847–857

    Article  CAS  PubMed  Google Scholar 

  • 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 17:5328–5337

    CAS  PubMed  Google Scholar 

  • Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174

    Article  CAS  PubMed  Google Scholar 

  • Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505–516

    Article  CAS  PubMed  Google Scholar 

  • 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 328:817–820

    Article  CAS  PubMed  Google Scholar 

  • 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 11:2547–2557

    CAS  PubMed  Google Scholar 

  • 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 68:4183–4191

    Article  CAS  PubMed  Google Scholar 

  • 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 11:1873–1878

    CAS  PubMed  Google Scholar 

  • 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–G285

    Article  CAS  PubMed  Google Scholar 

  • 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 57:3180–3188

    CAS  PubMed  Google Scholar 

  • 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 21:2418–2430

    Article  CAS  PubMed  Google Scholar 

  • Duh G, Mouri N, Warburton D, Thomas DW (2000) EGF regulates early embryonic mouse gut development in chemically defined organ culture. Pediatr Res 48:794–802

    Article  CAS  PubMed  Google Scholar 

  • Edwards DR, Handsley MM, Pennington CJ (2008) The ADAM metalloproteinases. Mol Aspects Med 29:258–289

    Article  CAS  PubMed  Google Scholar 

  • 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 65:3958–3965

    Article  CAS  PubMed  Google Scholar 

  • 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 27:225–231

    Article  CAS  PubMed  Google Scholar 

  • Fagin JA (2004) How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy. J Endocrinol 183:249–256

    Article  CAS  PubMed  Google Scholar 

  • Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284:14–30

    Article  CAS  PubMed  Google Scholar 

  • Fischer OM, Hart S, Gschwind A, Ullrich A (2003) EGFR signal transactivation in cancer cells. Biochem Soc Trans 31:1203–1208

    Article  CAS  PubMed  Google Scholar 

  • 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 300:505–516

    Article  CAS  PubMed  Google Scholar 

  • Freeman M (2004) Proteolysis within the membrane: rhomboids revealed. Nat Rev Mol Cell Biol 5:188–197

    Article  CAS  PubMed  Google Scholar 

  • 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 39:563–575

    Article  CAS  PubMed  Google Scholar 

  • Fuchs E (1990) Epidermal differentiation. Curr Opin Cell Biol 2:1028–1035

    Article  CAS  PubMed  Google Scholar 

  • Fuchs E (2008) Skin stem cells: rising to the surface. J Cell Biol 180:273–284

    Article  CAS  PubMed  Google Scholar 

  • 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 185:1243–1258

    Article  CAS  PubMed  Google Scholar 

  • 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 91:8132–8136

    Article  CAS  PubMed  Google Scholar 

  • 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 325:520–528

    Article  CAS  PubMed  Google Scholar 

  • 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):900–908

    Article  CAS  PubMed  Google Scholar 

  • 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 99:502–509

    Article  CAS  PubMed  Google Scholar 

  • 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 425–431

    Google Scholar 

  • 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 150:1959–1975

    CAS  PubMed  Google Scholar 

  • 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 60:3328–3332

    CAS  PubMed  Google Scholar 

  • Hashimoto K (2000) Regulation of keratinocyte function by growth factors. J Dermatol Sci 24 (Suppl) 1:S46–S50

    Google Scholar 

  • 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 269:20060–20066

    CAS  PubMed  Google Scholar 

  • Huang RP, Wu JX, Fan Y, Adamson ED (1996) UV activates growth factor receptors via reactive oxygen intermediates. J Cell Biol 133:211–220

    Article  CAS  PubMed  Google Scholar 

  • 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 314:3415–3425

    Article  CAS  PubMed  Google Scholar 

  • Hynes NE, Macdonald G (2009) ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21:177–184

    Article  CAS  PubMed  Google Scholar 

  • 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 40:92–97

    Article  PubMed  Google Scholar 

  • 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 189:22–32

    Article  CAS  PubMed  Google Scholar 

  • 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 77:25–79

    Article  CAS  PubMed  Google Scholar 

  • 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 15:5314–5325

    CAS  PubMed  Google Scholar 

  • Koch S, Nusrat A (2009) Dynamic regulation of epithelial cell fate and barrier function by intercellular junctions. Ann NY Acad Sci 1165:220–227

    Article  CAS  PubMed  Google Scholar 

  • 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 312:2791–2805

    Article  CAS  PubMed  Google Scholar 

  • 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 10:902–911

    Article  CAS  PubMed  Google Scholar 

  • Koster MI, Roop DR (2007) Mechanisms regulating epithelial stratification. Annu Rev Cell Dev Biol 23:93–113

    Article  CAS  PubMed  Google Scholar 

  • 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 274:15927–15936

    Article  CAS  PubMed  Google Scholar 

  • 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 37:251–259

    Article  CAS  PubMed  Google Scholar 

  • 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 129:491–495

    Article  CAS  PubMed  Google Scholar 

  • Lechler T, Fuchs E (2005) Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437:275–280

    Article  CAS  PubMed  Google Scholar 

  • 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 120:483–488

    Article  CAS  PubMed  Google Scholar 

  • Ley KD, Ellem KA (1992) UVC modulation of epidermal growth factor receptor number in HeLa S3 cells. Carcinogenesis 13:183–187

    Article  CAS  PubMed  Google Scholar 

  • 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 23:901–913

    Article  CAS  PubMed  Google Scholar 

  • 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 6:352–366

    Article  CAS  PubMed  Google Scholar 

  • 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 248:32–40

    Article  CAS  PubMed  Google Scholar 

  • 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 169:1402–1414

    Article  CAS  PubMed  Google Scholar 

  • 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 129:690–698

    Article  CAS  PubMed  Google Scholar 

  • 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 155:447–458

    Article  CAS  PubMed  Google Scholar 

  • 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 163:303–312

    CAS  PubMed  Google Scholar 

  • 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 376:337–341

    Article  CAS  PubMed  Google Scholar 

  • Minami S, Iwamoto R, Mekada E (2008) HB-EGF decelerates cell proliferation synergistically with TGFalpha in perinatal distal lung development. Dev Dyn 237:247–258

    Article  CAS  PubMed  Google Scholar 

  • 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 13:335–342

    CAS  PubMed  Google Scholar 

  • 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 106:9767–9772

    Article  CAS  PubMed  Google Scholar 

  • 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 14:5216–5223

    CAS  PubMed  Google Scholar 

  • Nakamura Y, Sotozono C, Kinoshita S (2001) The epidermal growth factor receptor (EGFR): role in corneal wound healing and homeostasis 5. Exp Eye Res 72:511–517

    Article  CAS  PubMed  Google Scholar 

  • 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 94:742–748

    Article  CAS  PubMed  Google Scholar 

  • 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 366:2–16

    Article  CAS  PubMed  Google Scholar 

  • 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–C10

    Article  CAS  PubMed  Google Scholar 

  • 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 274:17209–17218

    Article  CAS  PubMed  Google Scholar 

  • 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 6:605–617

    Article  CAS  PubMed  Google Scholar 

  • Pastore S, Mascia F, Mariani V, Girolomoni G (2008) The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol 128:1365–1374

    Article  CAS  PubMed  Google Scholar 

  • 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 12:745–760

    Article  CAS  PubMed  Google Scholar 

  • 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 295:93–101

    Article  CAS  PubMed  Google Scholar 

  • 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 141:802–810

    Article  CAS  PubMed  Google Scholar 

  • Radtke F, Raj K (2003) The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3:756–767

    Article  CAS  PubMed  Google Scholar 

  • Ren Z., Schaefer T.S. (2002). Erbs-s activates Stat3 alpha in a Src- and JAK2 dependent manner. J. Biol. Chem. 277:38486–38493

    Google Scholar 

  • 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 123:982–989

    Article  CAS  PubMed  Google Scholar 

  • 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 136:2153–2164

    Article  CAS  PubMed  Google Scholar 

  • 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 24:47–69

    Article  CAS  PubMed  Google Scholar 

  • 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 164:769–779

    Article  CAS  PubMed  Google Scholar 

  • Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225

    Article  CAS  PubMed  Google Scholar 

  • Schmidt E, Waschke J (2009) Apoptosis in pemphigus. Autoimmun Rev 8:533–537

    Article  CAS  PubMed  Google Scholar 

  • Sheng G, Bernabe KQ, Guo J, Warner BW (2006) Epidermal growth factor receptor-mediated proliferation of enterocytes requires p21waf1/cip1 expression. Gastroenterology 131:153–164

    Article  CAS  PubMed  Google Scholar 

  • 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 69:2568–2576

    Article  CAS  PubMed  Google Scholar 

  • Shilo BZ (2005) Regulating the dynamics of EGF receptor signaling in space and time. Development 132:4017–4027

    Article  CAS  PubMed  Google Scholar 

  • 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 275:5748–5753

    Article  CAS  PubMed  Google Scholar 

  • 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 102:211–220

    Article  CAS  PubMed  Google Scholar 

  • Sibilia M, Wagner EF (1995) Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269:234–238

    Article  CAS  PubMed  Google Scholar 

  • Singer AJ, Clark RA (1999) Cutaneous wound healing4. N Engl J Med 341:738–746

    Article  CAS  PubMed  Google Scholar 

  • 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 124:531–539

    Article  CAS  PubMed  Google Scholar 

  • 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 52:442–448

    Google Scholar 

  • 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 3:339–350

    Article  CAS  PubMed  Google Scholar 

  • 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 276:18265–18271

    Article  CAS  PubMed  Google Scholar 

  • Sundaram MV (2005) The love-hate relationship between Ras and Notch. Genes Dev 19:1825–1839

    Article  CAS  PubMed  Google Scholar 

  • 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 154:459–468

    Article  CAS  PubMed  Google Scholar 

  • 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 450:169–177

    Article  CAS  PubMed  Google Scholar 

  • 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 269:230–234

    Article  CAS  PubMed  Google Scholar 

  • 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 17:5948–5963

    Article  CAS  PubMed  Google Scholar 

  • 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 66:253–259

    Article  CAS  PubMed  Google Scholar 

  • Vincent A, Van SI (2009) Epigenetics, stem cells and epithelial cell fate. Differentiation 78(2–3):99–107

    Article  CAS  PubMed  Google Scholar 

  • 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 200:31–44

    Article  CAS  PubMed  Google Scholar 

  • 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 18:461–466

    CAS  PubMed  Google Scholar 

  • 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 269:9966–9973

    CAS  PubMed  Google Scholar 

  • 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 8:979–986

    Article  CAS  PubMed  Google Scholar 

  • Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines1. Physiol Rev 83:835–870

    CAS  PubMed  Google Scholar 

  • 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 4:650–658

    Article  CAS  PubMed  Google Scholar 

  • 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):615–624

    CAS  PubMed  Google Scholar 

  • 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 281:27389–27397

    Article  CAS  PubMed  Google Scholar 

  • 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 10:658–667

    Article  CAS  PubMed  Google Scholar 

  • Yarden Y, Shilo BZ (2007) SnapShot: EGFR signaling pathway. Cell 131:1018

    Article  PubMed  Google Scholar 

  • Yasmeen A, Bismar TA, Al Moustafa AE (2006) ErbB receptors and epithelial-cadherin-catenin complex in human carcinomas. Future Oncol 2:765–781

    Article  CAS  PubMed  Google Scholar 

  • 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 300:37–45

    Article  CAS  PubMed  Google Scholar 

  • 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 135:1137–1148

    Article  CAS  PubMed  Google Scholar 

  • Zorzou MP, Stratigos A, Efstathiou E, Bamias A (2004) Exacerbation of psoriasis after treatment with an EGFR tyrosine kinase inhibitor. Acta Derm Venereol 84:308–309

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biomedical Sciences, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE, 68178, USA

    Laura A. Hansen

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  1. Susan K. Repertinger
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  2. Justin G. Madson
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  3. Kyle J. Bichsel
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  4. Laura A. Hansen
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Correspondence to Laura A. Hansen .

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  1. Center for Molecular Toxicology &, Carcinogenesis, Pennsylvania State University, University Park, 16801, Pennsylvania, USA

    Adam B. Glick

  2. National Institute on Deafness &, Other Communication Disorders, National Institute of Health, Bethesda, 20892, Maryland, USA

    Carter Van Waes

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Repertinger, S.K., Madson, J.G., Bichsel, K.J., Hansen, L.A. (2011). The Epidermal Growth Factor Receptor in Normal and Neoplastic Epithelia. In: Glick, A., Waes, C. (eds) Signaling Pathways in Squamous Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7203-3_5

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