Signalling by the EGF receptor in human cancers: accentuate the positive, eliminate the negative

  • Haley L. Bennett
  • Tilman Brummer
  • Paul Timpson
  • Kate I. Patterson
  • Roger J. Daly
Part of the Cancer Drug Discovery and Development book series (CDD&D)


As described in accompanying chapters, enhanced EGF receptor (EGFR) signaling in human cancers can occur due to receptor overexpression or mutational activation. However, it may also arise from perturbations in the signal transduction pathways that function downstream of the receptor or the regulatory processes that tune the magnitude and duration of their output (Fig. 17.1). In this chapter we focus on the latter two aspects of oncogenic EGFR signaling. Specifically, we address: cancer-related changes that occur in the expression and/or activity of key signal relay molecules; pertubation of feedback control mechanisms; and attenuation of receptor down-regulation as a mechanism for signal amplification. We also discuss the impact of these changes on cellular sensitivity to EGFR-directed therapies, and how they inform more effective use of such therapies, alone or in combination with other signal transduction inhibitors, in a clinical setting.

Key words

Src Ras Raf Erk PI3-kinase PTEN feedback loops c-Cbl endocytosis EGFR inhibitors 


  1. 1.
    Burgess AW, Cho HS, Eigenbrot C, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003;12:541-552.Google Scholar
  2. 2.
    Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 2006;125:1137-1149.Google Scholar
  3. 3.
    Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103:211-225.Google Scholar
  4. 4.
    Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341-354.Google Scholar
  5. 5.
    Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006;7:505-516.Google Scholar
  6. 6.
    Ishizawar R, Parsons SJ. c-Src and cooperating partners in human cancer. Cancer Cell 2004;6:209-214.Google Scholar
  7. 7.
    Maa MC, Leu TH, McCarley DJ, Schatzman RC, Parsons SJ. Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: implications for the etiology of multiple human cancers. Proc Natl Acad Sci U S A 1995;92:6981-6985.Google Scholar
  8. 8.
    Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene 2000;19:5636-5642.Google Scholar
  9. 9.
    Cam WR, Masaki T, Shiratori Y, et al. Reduced C-terminal Src kinase activity is correlated inversely with pp60(c-src) activity in colorectal carcinoma. Cancer 2001;92:61-70.Google Scholar
  10. 10.
    Bjorge JD, Pang A, Fujita DJ. Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines. J Biol Chem 2000;275:41439-41446.Google Scholar
  11. 11.
    Irby RB, Mao W, Coppola D, et al. Activating SRC mutation in a subset of advanced human colon cancers. Nat Genet 1999;21:187-190.Google Scholar
  12. 12.
    Zhang SQ, Yang W, Kontaridis MI, et al. Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol Cell 2004;13:341-355.Google Scholar
  13. 13.
    Frame MC. Newest findings on the oldest oncogene; how activated src does it. J Cell Sci 2004;117:989-998.Google Scholar
  14. 14.
    Gonzalez L, Agullo-Ortuno MT, Garcia-Martinez JM, et al. Role of c-Src in human MCF7 breast cancer cell tumorigenesis. J Biol Chem 2006;281:20851-20864.Google Scholar
  15. 15.
    Alvarez RH, Kantarjian HM, Cortes JE. The role of Src in solid and hematologic malignancies: development of new-generation Src inhibitors. Cancer 2006;107:1918-1929.Google Scholar
  16. 16.
    Qin B, Ariyama H, Baba E, et al. Activated Src and Ras induce gefitinib resistance by activation of signaling pathways downstream of epidermal growth factor receptor in human gallbladder adenocarcinoma cells. Cancer Chemother Pharmacol 2006;58:577-584.Google Scholar
  17. 17.
    Hiscox S, Morgan L, Green TP, Barrow D, Gee J, Nicholson RI. Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. Breast Cancer Res Treat 2006;97:263-274.Google Scholar
  18. 18.
    Coopman PJ, Mueller SC. The Syk tyrosine kinase: a new negative regulator in tumor growth and progression. Cancer Lett 2006;241:159-173.Google Scholar
  19. 19.
    Ruschel A, Ullrich A. Protein tyrosine kinase Syk modulates EGFR signalling in human mammary epithelial cells. Cell Signal 2004;16:1249-1261.Google Scholar
  20. 20.
    Moroni M, Soldatenkov V, Zhang L, et al. Progressive loss of Syk and abnormal proliferation in breast cancer cells. Cancer Res 2004;64:7346-7354.Google Scholar
  21. 21.
    Rodriguez-Viciana P, Sabatier C, McCormick F. Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol Cell Biol 2004;24:4943-4954.Google Scholar
  22. 22.
    Daly RJ, Binder MD, Sutherland RL. Overexpression of the Grb2 gene in human breast cancer cell lines. Oncogene 1994;9:2723-2727.Google Scholar
  23. 23.
    Verbeek BS, Adriaansen-Slot SS, Rijksen G, Vroom TM. Grb2 overexpression in nuclei and cytoplasm of human breast cells: a histochemical and biochemical study of normal and neoplastic mammary tissue specimens. J Pathol 1997;183:195-203.Google Scholar
  24. 24.
    Yip SS, Crew AJ, Gee JM, et al. Up-regulation of the protein tyrosine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression. Int J Cancer 2000;88:363-368.Google Scholar
  25. 25.
    Lee MS, Igawa T, Chen SJ, et al. p66Shc protein is upregulated by steroid hormones in hormone-sensitive cancer cells and in primary prostate carcinomas. Int J Cancer 2004;108:672-678.Google Scholar
  26. 26.
    Rauh MJ, Blackmore V, Andrechek ER, et al. Accelerated mammary tumor development in mutant polyomavirus middle T transgenic mice expressing elevated levels of either the Shc or Grb2 adapter protein. Mol Cell Biol 1999;19:8169-8179.Google Scholar
  27. 27.
    Pelicci G, Lanfrancone L, Salcini AE, et al. Constitutive phosphorylation of Shc proteins in human tumors. Oncogene 1995;11:899-907.Google Scholar
  28. 28.
    Davol PA, Bagdasaryan R, Elfenbein GJ, Maizel AL, Frackelton AR, Jr. Shc proteins are strong, independent prognostic markers for both node-negative and node-positive primary breast cancer. Cancer Res 2003;63:6772-6783.Google Scholar
  29. 29.
    Jackson JG, Yoneda T, Clark GM, Yee D. Elevated levels of p66 Shc are found in breast cancer cell lines and primary tumors with high metastatic potential. Clin Cancer Res 2000;6:1135-1139.Google Scholar
  30. 30.
    Gu H, Neel BG. The “Gab” in signal transduction. Trends Cell Biol 2003;13:122-130.Google Scholar
  31. 31.
    Brummer T, Schramek D, Hayes VM, et al. Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein. J Biol Chem 2006;281:626-637.Google Scholar
  32. 32.
    Daly RJ, Gu H, Parmar J, et al. The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer. Oncogene 2002;21:5175-5181.Google Scholar
  33. 33.
    Bentires-Alj M, Gil SG, Chan R, et al. A role for the scaffolding adapter GAB2 in breast cancer. Nat Med 2006;12:114-121.Google Scholar
  34. 34.
    Schuuring E. The involvement of the chromosome 11q13 region in human malignancies: cyclin D1 and EMS1 are two new candidate oncogenes--a review. Gene 1995;159:83-96.Google Scholar
  35. 35.
    Sjoblom T, Jones S, Wood LD, et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006;314:268-274.Google Scholar
  36. 36.
    Bentires-Alj M, Paez JG, David FS, et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res 2004;64:8816-8820.Google Scholar
  37. 37.
    Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989;49:4682-4689.Google Scholar
  38. 38.
    Malaney S, Daly RJ. The ras signaling pathway in mammary tumorigenesis and metastasis. J Mammary Gland Biol Neoplasia 2001;6:101-113.Google Scholar
  39. 39.
    Han SW, Kim TY, Jeon YK, et al. Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res 2006;12:2538-2544.Google Scholar
  40. 40.
    Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339-346.Google Scholar
  41. 41.
    Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005;2:e17.Google Scholar
  42. 42.
    Giaccone G, Gallegos Ruiz M, Le Chevalier T, et al. Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res 2006;12:6049-6055.Google Scholar
  43. 43.
    Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66:3992-3995.Google Scholar
  44. 44.
    Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 2006;24:21-44.Google Scholar
  45. 45.
    Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol 2004;5:875-885.Google Scholar
  46. 46.
    Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949-954.Google Scholar
  47. 47.
    Sivaraman VS, Wang H, Nuovo GJ, Malbon CC. Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest 1997;99:1478-1483.Google Scholar
  48. 48.
    Schmidt CM, McKillop IH, Cahill PA, Sitzmann JV. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun 1997;236:54-58.Google Scholar
  49. 49.
    Normanno N, De Luca A, Maiello MR, et al. The MEK/MAPK pathway is involved in the resistance of breast cancer cells to the EGFR tyrosine kinase inhibitor gefitinib. J Cell Physiol 2006;207:420-427.Google Scholar
  50. 50.
    Gonzalez-Garcia A, Pritchard CA, Paterson HF, Mavria G, Stamp G, Marshall CJ. RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 2005;7:219-226.Google Scholar
  51. 51.
    Malliri A, van der Kammen RA, Clark K, van der Valk M, Michiels F, Collard JG. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 2002;417:867-871.Google Scholar
  52. 52.
    Bai Y, Edamatsu H, Maeda S, et al. Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development. Cancer Res 2004;64:8808-8810.Google Scholar
  53. 53.
    Camonis JH, White MA. Ral GTPases: corrupting the exocyst in cancer cells. Trends Cell Biol 2005;15:327-332.Google Scholar
  54. 54.
    Chien Y, Kim S, Bumeister R, et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 2006;127:157-170.Google Scholar
  55. 55.
    Sriuranpong V, Mutirangura A, Gillespie JW, et al. Global gene expression profile of nasopharyngeal carcinoma by laser capture microdissection and complementary DNA microarrays. Clin Cancer Res 2004;10:4944-4958.Google Scholar
  56. 56.
    Engers R, Mueller M, Walter A, Collard JG, Willers R, Gabbert HE. Prognostic relevance of Tiam1 protein expression in prostate carcinomas. Br J Cancer 2006;95:1081-1086.Google Scholar
  57. 57.
    Engers R, Zwaka TP, Gohr L, Weber A, Gerharz CD, Gabbert HE. Tiam1 mutations in human renal-cell carcinomas. Int J Cancer 2000;88:369-376.Google Scholar
  58. 58.
    Wells A, Grandis JR. Phospholipase C-gamma1 in tumor progression. Clin Exp Metastasis 2003;20:285-290.Google Scholar
  59. 59.
    Chen P, Xie H, Sekar MC, Gupta K, Wells A. 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 1994;127:847-857.Google Scholar
  60. 60.
    Thomas SM, Coppelli FM, Wells A, et al. Epidermal growth factor receptor-stimulated activation of phospholipase Cgamma-1 promotes invasion of head and neck squamous cell carcinoma. Cancer Res 2003;63:5629-5635.Google Scholar
  61. 61.
    Arteaga CL, Johnson MD, Todderud G, Coffey RJ, Carpenter G, Page DL. Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas. Proc Natl Acad Sci U S A 1991;88:10435-10439.Google Scholar
  62. 62.
    Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 2005;5:921-929.Google Scholar
  63. 63.
    Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006;6:184-192.Google Scholar
  64. 64.
    Stambolic V, Woodgett JR. Functional distinctions of protein kinase B/Akt isoforms defined by their influence on cell migration. Trends Cell Biol 2006;16:461-466.Google Scholar
  65. 65.
    Samuels Y, Ericson K. Oncogenic PI3K and its role in cancer. Curr Opin Oncol 2006;18:77-82.Google Scholar
  66. 66.
    Samuels Y, Velculescu VE. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 2004;3:1221-1224.Google Scholar
  67. 67.
    Bachman KE, Argani P, Samuels Y, et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 2004;3:772-775.Google Scholar
  68. 68.
    Levine DA, Bogomolniy F, Yee CJ, et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 2005;11:2875-2878.Google Scholar
  69. 69.
    Ikenoue T, Kanai F, Hikiba Y, et al. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 2005;65:4562-4567.Google Scholar
  70. 70.
    Isakoff SJ, Engelman JA, Irie HY, et al. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 2005;65:10992-11000.Google Scholar
  71. 71.
    Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM. The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci U S A 2005;102:18443-18448.Google Scholar
  72. 72.
    Philp AJ, Campbell IG, Leet C, et al. The phosphatidylinositol 3′-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 2001;61:7426-7429.Google Scholar
  73. 73.
    Shayesteh L, Lu Y, Kuo WL, et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 1999;21:99-102.Google Scholar
  74. 74.
    Yen CC, Chen YJ, Lu KH, et al. Genotypic analysis of esophageal squamous cell carcinoma by molecular cytogenetics and real-time quantitative polymerase chain reaction. Int J Oncol 2003;23:871-881.Google Scholar
  75. 75.
    Redon R, Muller D, Caulee K, Wanherdrick K, Abecassis J, du Manoir S. A simple specific pattern of chromosomal aberrations at early stages of head and neck squamous cell carcinomas: PIK3CA but not p63 gene as a likely target of 3q26-qter gains. Cancer Res 2001;61:4122-4129.Google Scholar
  76. 76.
    Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005;24:7455-7464.Google Scholar
  77. 77.
    Cheng JQ, Altomare DA, Klein MA, et al. Transforming activity and mitosis-related expression of the AKT2 oncogene: evidence suggesting a link between cell cycle regulation and oncogenesis. Oncogene 1997;14:2793-2801.Google Scholar
  78. 78.
    Arboleda MJ, Lyons JF, Kabbinavar FF, et al. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res 2003;63:196-206.Google Scholar
  79. 79.
    Irie HY, Pearline RV, Grueneberg D, et al. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol 2005;171:1023-1034.Google Scholar
  80. 80.
    Bellacosa A, de Feo D, Godwin AK, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 1995;64:280-285.Google Scholar
  81. 81.
    Bacus SS, Altomare DA, Lyass L, et al. AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival. Oncogene 2002;21:3532-3540.Google Scholar
  82. 82.
    Cheng JQ, Ruggeri B, Klein WM, et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A 1996;93:3636-3641.Google Scholar
  83. 83.
    Roy HK, Olusola BF, Clemens DL, et al. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 2002;23:201-205.Google Scholar
  84. 84.
    Xu X, Sakon M, Nagano H, et al. Akt2 expression correlates with prognosis of human hepatocellular carcinoma. Oncol Rep 2004;11:25-32.Google Scholar
  85. 85.
    Stal O, Perez-Tenorio G, Akerberg L, et al. Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res 2003;5:R37-44.Google Scholar
  86. 86.
    Nakatani K, Thompson DA, Barthel A, et al. Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J Biol Chem 1999;274:21528-21532.Google Scholar
  87. 87.
    Soung YH, Lee JW, Nam SW, Lee JY, Yoo NJ, Lee SH. Mutational Analysis of AKT1, AKT2 and AKT3 Genes in Common Human Carcinomas. Oncology 2006;70:285-289.Google Scholar
  88. 88.
    Chow LM, Baker SJ. PTEN function in normal and neoplastic growth. Cancer Lett 2006;241:184-196.Google Scholar
  89. 89.
    Leslie NR, Downes CP. PTEN function: how normal cells control it and tumour cells lose it. Biochem J 2004;382:1-11.Google Scholar
  90. 90.
    Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004;22:2954-2963.Google Scholar
  91. 91.
    Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 2005;65:2554-2559.Google Scholar
  92. 92.
    Knowles MA, Habuchi T, Kennedy W, Cuthbert-Heavens D. Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. Cancer Res 2003;63:7652-7656.Google Scholar
  93. 93.
    Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005;8:179-183.Google Scholar
  94. 94.
    Jiang WG, Sampson J, Martin TA, et al. Tuberin and hamartin are aberrantly expressed and linked to clinical outcome in human breast cancer: the role of promoter methylation of TSC genes. Eur J Cancer 2005;41:1628-1636.Google Scholar
  95. 95.
    Kataoka K, Fujimoto K, Ito D, et al. Expression and prognostic value of tuberous sclerosis complex 2 gene product tuberin in human pancreatic cancer. Surgery 2005;138:450-455.Google Scholar
  96. 96.
    Engelman JA, Janne PA, Mermel C, et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci U S A 2005;102:3788-3793.Google Scholar
  97. 97.
    Engelman JA, Mukohara T, Zejnullahu K, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest 2006;116:2695-2706.Google Scholar
  98. 98.
    Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353:2012-2024.Google Scholar
  99. 99.
    She QB, Solit D, Basso A, Moasser MM. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3′-kinase/Akt pathway signaling. Clin Cancer Res 2003;9:4340-4346.Google Scholar
  100. 100.
    Bianco R, Shin I, Ritter CA, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 2003;22:2812-2822.Google Scholar
  101. 101.
    Festuccia C, Muzi P, Millimaggi D, et al. Molecular aspects of gefitinib antiproliferative and pro-apoptotic effects in PTEN-positive and PTEN-negative prostate cancer cell lines. Endocr Relat Cancer 2005;12:983-998.Google Scholar
  102. 102.
    Wang MY, Lu KV, Zhu S, et al. Mammalian Target of Rapamycin Inhibition Promotes Response to Epidermal Growth Factor Receptor Kinase Inhibitors in PTEN-Deficient and PTEN-Intact Glioblastoma Cells. Cancer Res 2006;66:7864-7869.Google Scholar
  103. 103.
    Ferrell JE, Jr. Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr Opin Cell Biol 2002;14:140-148.Google Scholar
  104. 104.
    Courtois-Cox S, Genther Williams S, Reczek E, et al. A negative feedback signalling network underlies oncogene-induced senescence. Cancer Cell 2006;10:459-472.Google Scholar
  105. 105.
    O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-1508.Google Scholar
  106. 106.
    Northwood IC, Gonzalez FA, Wartmann M, Raden DL, Davis RJ. Isolation and characterization of two growth factor-stimulated protein kinases that phosphorylate the epidermal growth factor receptor at threonine 669. J Biol Chem 1991;266:15266-15276.Google Scholar
  107. 107.
    Theroux SJ, Taglienti-Sian C, Nair N, Countaway JL, Robinson HL, Davis RJ. Increased oncogenic potential of ErbB is associated with the loss of a COOH-terminal domain serine phosphorylation site. J Biol Chem 1992;267:7967-7970.Google Scholar
  108. 108.
    Huang L, Watanabe M, Chikamori M, et al. Unique role of SNT-2/FRS2beta/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways. Oncogene 2006;25:6457-6466.Google Scholar
  109. 109.
    Dougherty MK, Muller J, Ritt DA, et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell 2005;17:215-224.Google Scholar
  110. 110.
    Lynch DK, Daly RJ. PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2. Embo J 2002;21:72-82.Google Scholar
  111. 111.
    Bao L, Kimzey A, Sauter G, Sowadski JM, Lu KP, Wang DG. Prevalent overexpression of prolyl isomerase Pin1 in human cancers. Am J Pathol 2004;164:1727-1737.Google Scholar
  112. 112.
    Mason JM, Morrison DJ, Basson MA, Licht JD. Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling. Trends Cell Biol 2006;16:45-54.Google Scholar
  113. 113.
    Lo TL, Fong CW, Yusoff P, et al. Sprouty and cancer: The first terms report. Cancer Lett 2006;242:141-150.Google Scholar
  114. 114.
    Mason JM, Morrison DJ, Bassit B, et al. Tyrosine phosphorylation of Sprouty proteins regulates their ability to inhibit growth factor signaling: a dual feedback loop. Mol Biol Cell 2004;15:2176-2188.Google Scholar
  115. 115.
    Gur G, Rubin C, Katz M, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. Embo J 2004;23:3270-3281.Google Scholar
  116. 116.
    Suzuki Y, Miura H, Tanemura A, et al. Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia. FEBS Lett 2002;521:67-71.Google Scholar
  117. 117.
    Nilsson J, Vallbo C, Guo D, et al. Cloning, characterization, and expression of human LIG1. Biochem Biophys Res Commun 2001;284:1155-1161.Google Scholar
  118. 118.
    Holmlund C, Nilsson J, Guo D, et al. Characterization and tissue-specific expression of human LRIG2. Gene 2004;332:35-43.Google Scholar
  119. 119.
    Fiorini M, Ballaro C, Sala G, Falcone G, Alema S, Segatto O. Expression of RALT, a feedback inhibitor of ErbB receptors, is subjected to an integrated transcriptional and post-translational control. Oncogene 2002;21:6530-6539.Google Scholar
  120. 120.
    Anastasi S, Fiorentino L, Fiorini M, et al. Feedback inhibition by RALT controls signal output by the ErbB network. Oncogene 2003;22:4221-4234.Google Scholar
  121. 121.
    Xu D, Makkinje A, Kyriakis JM. Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function. J Biol Chem 2005;280:2924-2933.Google Scholar
  122. 122.
    Ferby I, Reschke M, Kudlacek O, et al. Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. Nat Med 2006;12:568-573.Google Scholar
  123. 123.
    Zhang YW, Staal B, Su Y, et al. Evidence that MIG-6 is a tumor-suppressor gene. Oncogene In press.Google Scholar
  124. 124.
    Anastasi S, Sala G, Huiping C, et al. Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin. Oncogene 2005;24:4540-4548.Google Scholar
  125. 125.
    Dickinson RJ, Keyse SM. Diverse physiological functions for dual-specificity MAP kinase phosphatases. J Cell Sci 2006;119:4607-4615.Google Scholar
  126. 126.
    Ryser S, Massiha A, Piuz I, Schlegel W. Stimulated initiation of mitogen-activated protein kinase phosphatase-1 (MKP-1) gene transcription involves the synergistic action of multiple cis-acting elements in the proximal promoter. Biochem J 2004;378:473-484.Google Scholar
  127. 127.
    Sato M, Vaughan MB, Girard L, et al. Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells. Cancer Res 2006;66:2116-2128.Google Scholar
  128. 128.
    Tsujita E, Taketomi A, Gion T, et al. Suppressed MKP-1 is an independent predictor of outcome in patients with hepatocellular carcinoma. Oncology 2005;69:342-347.Google Scholar
  129. 129.
    Furukawa T, Sunamura M, Motoi F, Matsuno S, Horii A. Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. Am J Pathol 2003;162:1807-1815.Google Scholar
  130. 130.
    Vicent S, Garayoa M, Lopez-Picazo JM, et al. Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell lung cancer and is an independent predictor of outcome in patients. Clin Cancer Res 2004;10:3639-3649.Google Scholar
  131. 131.
    Loda M, Capodieci P, Mishra R, et al. Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis. Am J Pathol 1996;149:1553-1564.Google Scholar
  132. 132.
    Liao Q, Guo J, Kleeff J, et al. Down-regulation of the dual-specificity phosphatase MKP-1 suppresses tumorigenicity of pancreatic cancer cells. Gastroenterology 2003;124:1830-1845.Google Scholar
  133. 133.
    Manzano RG, Montuenga LM, Dayton M, et al. CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential. Oncogene 2002;21:4435-4447.Google Scholar
  134. 134.
    Denkert C, Schmitt WD, Berger S, et al. Expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) in primary human ovarian carcinoma. Int J Cancer 2002;102:507-513.Google Scholar
  135. 135.
    Givant-Horwitz V, Davidson B, Goderstad JM, Nesland JM, Trope CG, Reich R. The PAC-1 dual specificity phosphatase predicts poor outcome in serous ovarian carcinoma. Gynecol Oncol 2004;93:517-523.Google Scholar
  136. 136.
    Sanchez-Perez I, Martinez-Gomariz M, Williams D, Keyse SM, Perona R. CL100/MKP-1 modulates JNK activation and apoptosis in response to cisplatin. Oncogene 2000;19:5142-5152.Google Scholar
  137. 137.
    Small GW, Shi YY, Edmund NA, Somasundaram S, Moore DT, Orlowski RZ. Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an antiapoptotic role. Mol Pharmacol 2004;66:1478-1490.Google Scholar
  138. 138.
    Schulze A, Lehmann K, Jefferies HB, McMahon M, Downward J. Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev 2001;15:981-994.Google Scholar
  139. 139.
    Berset TA, Hoier EF, Hajnal A. The C. elegans homolog of the mammalian tumor suppressor Dep-1/Scc1 inhibits EGFR signaling to regulate binary cell fate decisions. Genes Dev 2005;19:1328-1340.Google Scholar
  140. 140.
    Ruivenkamp CA, van Wezel T, Zanon C, et al. Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nat Genet 2002;31:295-300.Google Scholar
  141. 141.
    Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature 2002;416:183-187.Google Scholar
  142. 142.
    Petrelli A, Gilestro GF, Lanzardo S, Comoglio PM, Migone N, Giordano S. The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature 2002;416:187-190.Google Scholar
  143. 143.
    Lynch DK, Winata SC, Lyons RJ, et al. A Cortactin-CD2-associated Protein (CD2AP) Complex Provides a Novel Link between Epidermal Growth Factor Receptor Endocytosis and the Actin Cytoskeleton. J Biol Chem 2003;278:21805-21813.Google Scholar
  144. 144.
    Marmor MD, Yarden Y. Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene 2004;23:2057-2070.Google Scholar
  145. 145.
    Thien CB, Langdon WY. Cbl: many adaptations to regulate protein tyrosine kinases. Nat Rev Mol Cell Biol 2001;2:294-307.Google Scholar
  146. 146.
    Thien CB, Walker F, Langdon WY. RING finger mutations that abolish c-Cbl-directed polyubiquitination and downregulation of the EGF receptor are insufficient for cell transformation. Mol Cell 2001;7:355-365.Google Scholar
  147. 147.
    Waterman H, Katz M, Rubin C, et al. A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling. Embo J 2002;21:303-313.Google Scholar
  148. 148.
    Moscatello DK, Holgado-Madruga M, Godwin AK, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 1995;55:5536-5539.Google Scholar
  149. 149.
    Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 2000;60:1383-1387.Google Scholar
  150. 150.
    Schmidt MH, Furnari FB, Cavenee WK, Bogler O. Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization. Proc Natl Acad Sci U S A 2003;100:6505-6510.Google Scholar
  151. 151.
    Lenferink AE, Pinkas-Kramarski R, van de Poll ML, et al. Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. Embo J 1998;17:3385-3397.Google Scholar
  152. 152.
    Worthylake R, Opresko LK, Wiley HS. ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem 1999;274:8865-8874.Google Scholar
  153. 153.
    Muthuswamy SK, Gilman M, Brugge JS. Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol 1999;19:6845-6857.Google Scholar
  154. 154.
    Bao J, Gur G, Yarden Y. Src promotes destruction of c-Cbl: implications for oncogenic synergy between Src and growth factor receptors. Proc Natl Acad Sci U S A 2003;100:2438-2443.Google Scholar
  155. 155.
    Tanos B, Pendergast AM. Abl tyrosine kinase regulates endocytosis of the epidermal growth factor receptor. J Biol Chem 2006;281:32714-32723.Google Scholar
  156. 156.
    Chen WS, Kung HJ, Yang WK, Lin W. Comparative tyrosine-kinase profiles in colorectal cancers: enhanced arg expression in carcinoma as compared with adenoma and normal mucosa. Int J Cancer 1999;83:579-584.Google Scholar
  157. 157.
    Srinivasan D, Plattner R. Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells. Cancer Res 2006;66:5648-5655.Google Scholar
  158. 158.
    Feng Q, Baird D, Peng X, et al. Cool-1 functions as an essential regulatory node for EGF receptor- and Src-mediated cell growth. Nat Cell Biol 2006;8:945-956.Google Scholar
  159. 159.
    Fritz G, Just I, Kaina B. Rho GTPases are over-expressed in human tumors. Int J Cancer 1999;81:682-687.Google Scholar
  160. 160.
    Qiu RG, Abo A, McCormick F, Symons M. Cdc42 regulates anchorage-independent growth and is necessary for Ras transformation. Mol Cell Biol 1997;17:3449-3458.Google Scholar
  161. 161.
    Wu WJ, Tu S, Cerione RA. Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation. Cell 2003;114:715-725.Google Scholar
  162. 162.
    Hirsch DS, Shen Y, Wu WJ. Growth and motility inhibition of breast cancer cells by epidermal growth factor receptor degradation is correlated with inactivation of Cdc42. Cancer Res 2006;66:3523-3530.Google Scholar
  163. 163.
    Zhang B, Srirangam A, Potter DA, Roman A. HPV16 E5 protein disrupts the c-Cbl-EGFR interaction and EGFR ubiquitination in human foreskin keratinocytes. Oncogene 2005;24:2585-2588.Google Scholar
  164. 164.
    Daly RJ. Cortactin signalling and dynamic actin networks. Biochem J 2004;382:13-25.Google Scholar
  165. 165.
    Timpson P, Lynch DK, Schramek D, Walker F, Daly RJ. Cortactin overexpression inhibits ligand-induced down-regulation of the epidermal growth factor receptor. Cancer Res 2005;65:3273-3280.Google Scholar
  166. 166.
    Hyun TS, Rao DS, Saint-Dic D, et al. HIP1 and HIP1r stabilize receptor tyrosine kinases and bind 3-phosphoinositides via epsin N-terminal homology domains. J Biol Chem 2004;279:14294-14306.Google Scholar
  167. 167.
    Rao DS, Bradley SV, Kumar PD, et al. Altered receptor trafficking in Huntingtin Interacting Protein 1-transformed cells. Cancer Cell 2003;3:471-482.Google Scholar
  168. 168.
    Rao DS, Hyun TS, Kumar PD, et al. Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival. J Clin Invest 2002;110:351-360.Google Scholar
  169. 169.
    Lee MP, Feinberg AP. Aberrant splicing but not mutations of TSG101 in human breast cancer. Cancer Res 1997;57:3131-3134.Google Scholar
  170. 170.
    Xu Z, Liang L, Wang H, Li T, Zhao M. HCRP1, a novel gene that is downregulated in hepatocellular carcinoma, encodes a growth-inhibitory protein. Biochem Biophys Res Commun 2003;311:1057-1066.Google Scholar
  171. 171.
    Bache KG, Slagsvold T, Cabezas A, Rosendal KR, Raiborg C, Stenmark H. The growth-regulatory protein HCRP1/hVps37A is a subunit of mammalian ESCRT-I and mediates receptor down-regulation. Mol Biol Cell 2004;15:4337-4346.Google Scholar
  172. 172.
    Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 2005;102:7665-7670.Google Scholar
  173. 173.
    Ono M, Hirata A, Kometani T, et al. Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. Mol Cancer Ther 2004;3:465-472.Google Scholar
  174. 174.
    Adjei AA. Novel combinations based on epidermal growth factor receptor inhibition. Clin Cancer Res 2006;12:4446s-4450s.Google Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Haley L. Bennett
    • 1
  • Tilman Brummer
    • 1
  • Paul Timpson
    • 1
  • Kate I. Patterson
    • 1
  • Roger J. Daly
    • 1
  1. 1.Cancer Research ProgramGarvan Institute of Medical ResearchSydneyAustralia

Personalised recommendations