Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

EGF–ERBB signalling: towards the systems level

Key Points

  • The ERBB system consists of four receptors (ERBB1–4), two of which, ERBB2/HER2 and ERBB3 are non-autonomous. All four ERBB proteins form functional dimers after activation by epidermal growth factor (EGF)-family growth factors.

  • Recent advances in structural analysis of the receptors has revealed the mechanism of receptor dimerization, and together with the results of gene targeting in mice provide an explanation for the critical role of ERBB2/HER2 in human cancer.

  • Misregulated activation of ERBB receptors has been widely associated with human malignancies, and a number of drugs that target these receptors are in clinical use.

  • 25,000 scientific papers relate to ERBB-receptor signalling, in which hundreds of receptor interactions are described, forcing investigators to take a systems view of the network.

  • Definitions from the field of systems biology apply to the ERBB network, which is described as a robust information-processing system, with a bow-tie structure, to which we apply principles of modularity, redundancy, bistability, system controls and buffering.

  • Fragility of the system is a necessary trade-off of its robustness, a principle we exemplify when dealing with clinically approved, as well as experimental, cancer therapeutics.

  • Future analysis of the ERBB network might depend on establishing common experimental conditions, which will allow synergistic interactions between experimentalists and theoreticians in the field.

Abstract

Signalling through the ERBB/HER receptors is intricately involved in human cancer and already serves as a target for several cancer drugs. Because of its inherent complexity, it is useful to envision ERBB signalling as a bow-tie-configured, evolvable network, which shares modularity, redundancy and control circuits with robust biological and engineered systems. Because network fragility is an inevitable trade-off of robustness, systems-level understanding is expected to generate therapeutic opportunities to intercept aberrant network activation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A systems perspective of the ERBB network.
Figure 2: Structural basis for ERBB-receptor dimerization and activation.
Figure 3: Endocytosis and nuclear translocation of ERBB proteins.
Figure 4: Multiple pathways to oncogenesis.

Similar content being viewed by others

References

  1. Klapper, L. N. et al. The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc. Natl Acad. Sci. USA 96, 4995–5000 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Guy, P. M., Platko, J. V., Cantley, L. C., Cerione, R. A. & Carraway, K. L. 3rd. Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc. Natl Acad. Sci. USA 91, 8132–8136 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127–137 (2001).

    Article  CAS  Google Scholar 

  4. Stelling, J., Sauer, U., Szallasi, Z., Doyle, F. J. 3rd & Doyle, J. Robustness of cellular functions. Cell 118, 675–685 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Kitano, H. Biological robustness. Nature Rev. Genet. 5, 826–837 (2004). An introductory text to systems biology that describes the principles of robustness in biological systems.

    Article  CAS  PubMed  Google Scholar 

  6. Schulze, W. X., Deng, L. & Mann, M. Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol. Syst. Biol. 1, 42–54 (2005).

    Article  CAS  Google Scholar 

  7. Levkowitz, G. et al. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol. Cell 4, 1029–1040 (1999). Identified c-Cbl as the phospho-activated ubiquitin-ligase that mediates EGF-receptor degradation.

    Article  CAS  PubMed  Google Scholar 

  8. Miettinen, P. J. et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Threadgill, D. W. et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269, 230–234 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Sibilia, M. & Wagner, E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Sibilia, M., Steinbach, J. P., Stingl, L., Aguzzi, A. & Wagner, E. F. A strain-independent postnatal neurodegeneration in mice lacking the EGF receptor. EMBO J. 17, 719–731 (1998).References 8–11 describe the phenotypes of Egfr knockouts that show variable defects depending on genetic background.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Luetteke, N. C. et al. Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development 126, 2739–2750 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Mann, G. et al. Mice with null mutations of the TGFα gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation. Cell 73, 249–261 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Troyer, K. L. et al. Growth retardation, duodenal lesions, and aberrant ileum architecture in triple null mice lacking EGF, amphiregulin, and TGF-α. Gastroenterology 121, 68–78 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Luetteke, N. C. et al. TGFα deficiency results in hair follicles and eye abnormalities in targeted and waved-1 mice. Cell 73, 263–278 (1993). References 12–15 describe the phenotypes of knockouts of EGFR ligands, which are milder than the phenotype of the EGFR knockout.

    Article  CAS  PubMed  Google Scholar 

  16. Luetteke, N. C. et al. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Dev. 8, 399–413 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Tzahar, E. et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol. Cell. Biol. 16, 5276–5287 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jones, R. B., Gordus, A., Krall, J. A. & Macbeath, G. A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 439, 168–174 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Baulida, J., Kraus, M. H., Alimandi, M., Di Fiore, P. P. & Carpenter, G. All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J. Biol. Chem. 271, 5251–5257 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Worthylake, R., Opresko, L. K. & Wiley, H. S. ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J. Biol. Chem. 274, 8865–8874 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Lenferink, A. E. et al. Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. EMBO J. 17, 3385–3397 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pinkas-Kramarski, R. et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J. 15, 2452–2467 (1996). Shows that ERBB2, rather than functioning as an autonomous, ligand-activated receptor, is a shared co-receptor that amplifies the signalling potential of the other ERBBs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Waterman, H., Alroy, I., Strano, S., Seger, R. & Yarden, Y. The C-terminus of the kinase-defective neuregulin receptor ErbB-3 confers mitogenic superiority and dictates endocytic routing. EMBO J. 18, 3348–3358 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wallasch, C. et al. Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J. 14, 4267–4275 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Srinivisan, R., Poulsom, R., Hurst, H. C. & Gullick, W. Expression of the c-erbB-4/HER4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types. J. Pathol. 185, 236–245 (1998).

    Article  Google Scholar 

  26. Rio, C., Buxbaum, J. D., Peschon, J. J. & Corfas, G. Tumor necrosis factor-α-converting enzyme is required for cleavage of erbB4/HER4. J. Biol. Chem. 275, 10379–10387 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Elenius, K. et al. Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase. Oncogene 18, 2607–2615 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Ni, C. Y., Murphy, M. P., Golde, T. E. & Carpenter, G. γ-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179–2181 (2001). Description of ERBB4 cleavage that leads to formation of a soluble intracellular domain, which might function independently of the membrane-associated receptor.

    Article  CAS  PubMed  Google Scholar 

  29. Meyer, D. & Birchmeier, C. Multiple essential functions of neuregulin in development. Nature 378, 386–390 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Lee, K. F. et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378, 394–398 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Gassmann, M. et al. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378, 390–394 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Riethmacher, D. et al. Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389, 725–730 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Burgess, A. W. et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell 12, 541–552 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Gadella, T. W. & Jovin, T. M. Oligomerization of epidermal growth factor receptors on A431 cells studied by time-resolved fluorescence imaging microscopy. A stereochemical model for tyrosine kinase receptor activation. J. Cell Biol. 129, 1543–1558 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Lemmon, M. A. et al. Two EGF molecules contribute additively to stabilization of the EGFR dimer. EMBO J. 16, 281–294 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sako, Y., Minoghchi, S. & Yanagida, T. Single-molecule imaging of EGFR signalling on the surface of living cells. Nature Cell Biol. 2, 168–172 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Moriki, T., Maruyama, H. & Maruyama, I. N. Activation of preformed EGF receptor dimers by ligand-induced rotation of the transmembrane domain. J. Mol. Biol. 311, 1011–1026 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Clayton, A. H. et al. Ligand-induced dimer–tetramer transition during the activation of the cell surface epidermal growth factor receptor-A-multidimensional microscopy analysis. J. Biol. Chem. 280, 30392–30399 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Garrett, T. P. et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha. Cell 110, 763–773 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Ogiso, H. et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110, 775–787 (2002). References 39 and 40 describe the structures of the ligand-bound extracellular domain of the EGFR and reveal the basis of ligand-induced receptor activation.

    Article  CAS  PubMed  Google Scholar 

  41. Garrett, T. P. et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol. Cell 11, 495–505 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Blagoev, B., Ong, S. E., Kratchmarova, I. & Mann, M. Temporal analysis of phosphotyroisne-dependent signaling networks by quantitative proteomics. Nature Biotechnol. 22, 1139–1145 (2004). Demonstration of the power of new high-throughput techniques for accumulation of quantitative information regarding signalling events.

    Article  CAS  Google Scholar 

  43. Zhang, Y. et al. Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules. Mol. Cell. Proteomics 4, 1240–1250 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Ma, H. W. & Zeng, A. P. The connectivity structure, giant strong component and centrality of metabolic networks. Bioinformatics 19, 1423–1430 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Kirschner, M. & Gerhart, J. Evolvability. Proc. Natl Acad. Sci. USA 95, 8420–8427 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Agrawal, A. A. Phenotypic plasticity in the interactions and evolution of species. Science 294, 321–326 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Okutani, T. et al. Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cells. J. Biol. Chem. 269, 31310–31314 (1994).

    Article  CAS  PubMed  Google Scholar 

  48. Batzer, A. G., Rotin, D., Urena, J. M., Skolnik, E. Y. & Schlessinger, J. Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Mol. Cell. Biol. 14, 5192–5201 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Waterman, H. et al. A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling. EMBO J. 21, 303–313 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jiang, X., Huang, F., Marusyk, A. & Sorkin, A. Grb2 Regulates Internalization of EGF receptors through clathrin-coated pits. Mol. Biol. Cell. 14, 858–870 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Freeman, M. Feedback control of intercellular signalling in development. Nature 408, 313–319 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Schulze, A., Lehmann, K., Jefferies, H. B., McMahon, M. & Downward, J. Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev. 15, 981–994 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schafer, B., Gschwind, A. & Ullrich, A. Multiple G-protein-coupled receptor signals converge on the epidermal growth factor receptor to promote migration and invasion. Oncogene 23, 991–999 (2004).

    Article  PubMed  CAS  Google Scholar 

  54. Wiley, H. S. Trafficking of the ErbB receptors and its influence on signaling. Exp. Cell Res. 284, 78–88 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Berset, T. A., Hoier, E. F. & 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. 19, 1328–1340 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Haj, F. G., Verveer, P. J., Squire, A., Neel, B. G. & Bastiaens, P. I. Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science 295, 1708–1711 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Kario, E. et al. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J. Biol. Chem. 280, 7038–7048 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Hanafusa, H., Torii, S., Yasunaga, T. & Nishida, E. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signaling pathway. Nature Cell Biol. 4, 850–858 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Reich, A., Sapir, A. & Shilo, B. Sprouty is a general inhibitor of receptor tyrosine kinase signaling. Development 126, 4139–4147 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Yusoff, P. et al. Sprouty2 inhibits the Ras/MAP kinase pathway by inhibiting the activation of Raf. J. Biol. Chem. 277, 3195–3201 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Rubin, C. et al. Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops. Curr. Biol. 13, 297–307 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Laederich, M. B. et al. The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J. Biol. Chem. 279, 47050–47056 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Gur, G. et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. EMBO J. 23, 3270–3281 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hackel, P. O., Gishizky, M. & Ullrich, A. Mig-6 is a negative regulator of the epidermal growth factor receptor signal. Biol. Chem. 382, 1649–1662 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Fiorini, M. et al. Expression of RALT, a feedback inhibitor of ErbB receptors, is subjected to an integrated transcriptional and post-translational control. Oncogene 21, 6530–6539 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Anastasi, S. et al. Feedback inhibition by RALT controls signal output by the ErbB network. Oncogene 22, 4221–4234 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. Neckers, L. & Ivy, S. P. Heat shock protein 90. Curr. Opin. Oncol. 15, 419–424 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Citri, A., Kochupurakkal, B. S. & Yarden, Y. The Achilles heel of ErbB-2/HER2: regulation by the Hsp90 chaperone machine and potential for pharmacological intervention. Cell Cycle 3, 51–60 (2003).

    Google Scholar 

  70. Mimnaugh, E. G., Chavany, C. & Neckers, L. Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J. Biol. Chem. 271, 22796–22801 (1996). Early evidence which shows that HSP90 is a regulator of the ERBB network by modulating the stability of ERBB2.

    Article  CAS  PubMed  Google Scholar 

  71. Citri, A. et al. Hsp90 restrains ErbB-2/HER2 signalling by limiting heterodimer formation. EMBO Rep. 5, 1165–1170 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tikhomirov, O. & Carpenter, G. Identification of ErbB-2 kinase domain motifs required for geldanamycin-induced degradation. Cancer Res. 63, 39–43 (2003).

    CAS  PubMed  Google Scholar 

  73. Xu, W. et al. Surface charge and hydrophobicity determine ErbB2 binding to the Hsp90 chaperone complex. Nature Struct. Mol. Biol. 12, 120–126 (2005).

    Article  CAS  Google Scholar 

  74. Wang, Q., Villeneuve, G. & Wang, Z. Control of epidermal growth factor receptor endocytosis by receptor dimerization, rather than receptor kinase activation. EMBO Rep. 6, 942–948 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Opresko, L. K. et al. Endocytosis and lysosomal targeting of epidermal growth factor receptors are mediated by distinct sequences independent of the tyrosine kinase domain. J. Biol. Chem. 270, 4325–4333 (1995).

    Article  CAS  PubMed  Google Scholar 

  76. Honegger, A., M. et al. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing. Cell 51, 199–209 (1987).

    Article  CAS  PubMed  Google Scholar 

  77. Herbst, J. J., Opresko, L. K., Walsh, B. J., Lauffenburger, D. A. & Wiley, H. S. Regulation of postendocytic trafficking of the epidermal growth factor receptor through endosomal retention. J. Biol. Chem. 269, 12865–12873 (1994).

    Article  CAS  PubMed  Google Scholar 

  78. Marmor, M. D. & Yarden, Y. Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene 23, 2057–2070 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Wang, Z. & Moran, M. F. Requirement for the adapter protein GRB2 in EGF receptor endocytosis. Science 272, 1935–1938 (1996).

    Article  CAS  PubMed  Google Scholar 

  80. Petrelli, A. et al. The endophilin–CIN85–Cbl complex mediates ligand-dependent downregulation of c-Met. Nature 416, 187–190 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Soubeyran, P., Kowanetz, K., Szymkiewicz, I., Langdon, W. Y. & Dikic, I. Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature 416, 183–187 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Katz, M. et al. Ligand-independent degradation of epidermal growth factor receptor involves receptor ubiquitylation and Hgs, an adaptor whose ubiquitin-interacting motif targets ubiquitylation by Nedd4. Traffic 3, 740–751 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Polo, S. et al. A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416, 451–455 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Amit, I. et al. Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding. Genes Dev. 18, 1737–1752 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Katzmann, D. J., Odorizzi, G. & Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell. Biol. 3, 893–905 (2002).

    Article  CAS  Google Scholar 

  86. Di Guglielmo, G. M., Baass, P. C., Ou, W. J., Posner, B. I. & Bergeron, J. J. Compartmentalization of SHC, GRB2 and mSOS, and hyperphosphorylation of Raf-1 by EGF but not insulin in liver parenchyma. EMBO J. 13, 4269–4277 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wang, Y., Pennock, S., Chen, X. & Wang, Z. Endosomal signaling of epidermal growth factor receptor stimulates signal transduction pathways leading to cell survival. Mol. Cell. Biol. 22, 7279–7290 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Miaczynska, M. et al. APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell 116, 445–456 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Vecchi, M., Baulida, J. & Carpenter, G. Selective cleavage of the heregulin receptor ErbB-4 by protein kinase C activation. J. Biol. Chem. 271, 18989–18995 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Williams, C. C. et al. The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone. J. Cell. Biol. 167, 469–478 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Komuro, A., Nagai, M., Navin, N. E. & Sudol, M. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J. Biol. Chem. 278, 33334–33341 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Omerovic, J. et al. Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level. Exp. Cell Res. 294, 469–479 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Aqeilan, R. I. et al. WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res. 65, 6764–6772 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Wang, S. C. et al. Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell 6, 251–261 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Lo, H. W. et al. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell 7, 575–589 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Kholodenko, B. N. Cell signalling dynamics in time and space. Nature Rev. Mol. Cell. Biol. 7, 165–176 (2006).

    Article  CAS  Google Scholar 

  97. Orton, R. J. et al. Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway. Biochem. J. 392, 249–261 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wiley, H. S. & Cunningham, D. D. A steady state model for analyzing the cellular binding, internalization and degradation of polypeptide ligands. Cell 25, 433–440 (1981).

    Article  CAS  PubMed  Google Scholar 

  99. Starbuck, C. & Lauffenburger, D. A. Mathematical model for the effects of epidermal growth factor receptor trafficking dynamics on fibroblast proliferation responses. Biotechnol. Prog. 8, 132–143 (1992).

    Article  CAS  PubMed  Google Scholar 

  100. Wiley, H. S. et al. The role of tyrosine kinase activity in endocytosis, compartmentation, and down-regulation of the epidermal growth factor receptor. J. Biol. Chem. 266, 11083–11094 (1991).

    Article  CAS  PubMed  Google Scholar 

  101. Kholodenko, B. N., Demin, O. V., Moehren, G. & Hoek, J. B. Quantification of short term signaling by the epidermal growth factor receptor. J. Biol. Chem. 274, 30169–30181 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Schoeberl, B., Eichler-Jonsson, C., Gilles, E. D. & Muller, G. Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors. Nature Biotechnol. 20, 370–375 (2002). References 101 and 102 describe the first attempts to formulate models of the early events following activation of the EGFR. These two models function as platforms for developing more complex models of EGFR signalling.

    Article  Google Scholar 

  103. Resat, H., Ewald, J. A., Dixon, D. A. & Wiley, H. S. An integrated model of epidermal growth factor receptor trafficking and signal transduction. Biophys. J. 85, 730–743 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Maly, I. V., Wiley, H. S. & Lauffenburger, D. A. Self-organization of polarized cell signaling via autocrine circuits: computational model analysis. Biophys. J. 86, 10–22 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Oda, K., Matsuoka, Y., Funahashi, A. & Kitano, H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol. Syst. Biol. 1, 8–24 (2005).

    Article  CAS  Google Scholar 

  106. Reddy, C. C., Niyogi, S. K., Wells, A., Wiley, H. S. & Lauffenburger, D. A. Engineering epidermal growth factor for enhanced mitogenic potency. Nature Biotech. 14, 1696–1699 (1996).

    Article  CAS  Google Scholar 

  107. Tzahar, E. et al. Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network. EMBO J. 17, 5948–5963 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Haugh, J. M. & Lauffenburger, D. A. Analysis of receptor internalization as a mechanism for modulating signal transduction. J. Theoret. Biol. 195, 187–218 (1998).

    Article  CAS  Google Scholar 

  109. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Pao, W. et al. EGF receptor gene mutations are common in lung cancers from 'never smokers' and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306–13311 (2004). References 109–111 describe identification of activating mutations within the kinase domain of the EGFR. Patients whose tumours bear these mutations respond better to treatment with EGFR-specific kinase inhibitors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tracy, S. et al. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res. 64, 7241–7244 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Sordella, R., Bell, D. W., Haber, D. A. & Settleman, J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305, 1163–1167 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Engelman, J. A. et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc. Natl Acad. Sci. USA 102, 3788–3793 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Shigematsu, H. et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 65, 1642–1646 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Ekstrand, A. J., Sugawa, N., James, C. D. & Collins, V. P. Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc. Natl Acad. Sci. USA 89, 4309–4313 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ekstrand, A. J. et al. Genes for epidermal growth factor receptor, transforming growth factor α, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res. 51, 2164–2172 (1991).

    CAS  PubMed  Google Scholar 

  118. Liu, L. et al. Clinical significance of EGFR amplification and the aberrant EGFRvIII transcript in conventionally treated astrocytic gliomas. J. Mol. Med. 83, 917–926 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Huang, H. S. et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J. Biol. Chem. 272, 2927–2935 (1997).

    Article  CAS  PubMed  Google Scholar 

  120. Nicholson, R. I., Gee, J. M. & Harper, M. E. EGFR and cancer prognosis. Eur. J. Cancer 37 (Suppl. 4), S9–S15 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Ford, A. C. & Grandis, J. R. Targeting epidermal growth factor receptor in head and neck cancer. Head Neck 25, 67–73 (2003).

    Article  PubMed  Google Scholar 

  122. Ross, J. S. et al. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 8, 307–325 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Slamon, D. J. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712 (1989). The first study to show that ERBB2 amplification predicts poor prognosis for breast cancer patients.

    Article  CAS  PubMed  Google Scholar 

  124. Hirai, T. et al. Clinical results of transhiatal esophagectomy for carcinoma of the lower thoracic esophagus according to biological markers. Dis. Esophagus 11, 221–225 (1998).

    Article  CAS  PubMed  Google Scholar 

  125. Tateishi, M., Ishida, T., Mitsudomi, T., Kaneko, S. & Sugimachi, K. Immunohistochemical evidence of autocrine growth factors in adenocarcinoma of the human lung. Cancer Res. 12, 1183–1188 (1990).

    Google Scholar 

  126. Hansen, M. R., Roehm, P. C., Chatterjee, P. & Green, S. H. Constitutive neuregulin-1/ErbB signaling contributes to human vestibular schwannoma proliferation. Glia 53, 593–600 (2006).

    Article  PubMed  Google Scholar 

  127. Moghal, N. & Sternberg, P. W. The epidermal growth factor system in Caenorhabditis elegans. Exp. Cell Res. 284, 150–159 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Shilo, B. Z. Signaling by the Drosophila epidermal growth factor receptor pathway during development. Exp. Cell Res. 284, 140–149 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Stein, R. A. & Staros, J. V. Evolutionary analysis of the ErbB receptor and ligand families. J. Mol. Evol. 50, 397–412 (2000).

    Article  CAS  PubMed  Google Scholar 

  130. Bray, D. & Lay, S. Computer simulated evolution of a network of cell-signaling molecules. Biophys. J. 66, 972–977 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Kitano, H. Cancer robustness: tumour tactics. Nature 426, 125 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Carlson, J. M. & Doyle, J. Highly optimized tolerance: robustness and design in complex systems. Phys. Rev. Lett. 84, 2529–2532 (2000).

    Article  CAS  PubMed  Google Scholar 

  133. Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nature Med. 6, 443–446 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Nagata, Y. et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6, 117–127 (2004).

    Article  CAS  PubMed  Google Scholar 

  135. Spiridon, C. I. et al. Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo. Clin. Cancer Res. 8, 1720–1730 (2002).

    CAS  PubMed  Google Scholar 

  136. Friedman, L. M. et al. Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc. Natl Acad. Sci. USA 102, 1915–1920 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Xia, W. et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21, 6255–6263 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Citri, A. et al. Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. EMBO J. 21, 2407–2417 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Goldie, J. H. & Coldman, A. J. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat. Rep. 63, 1727–1733 (1979).

    CAS  PubMed  Google Scholar 

  140. Ye, D., Mendelsohn, J. & Fan, Z. Augmentation of a humanized anti-HER2 mAb 4D5 induced growth inhibition by a human–mouse chimeric anti-EGF receptor mAb C225. Oncogene 18, 731–738 1999).

    Article  CAS  PubMed  Google Scholar 

  141. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Article  CAS  PubMed  Google Scholar 

  142. Shou, J. et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J. Natl Cancer Inst. 96, 926–935 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank B. Kholodenko, S. H. Wiley, M. Hatakeyama and P. De-Meyts for insightful comments. Our laboratory is supported by research grants from the National Cancer Institute, the Israel Science Foundation, the Israel Cancer Research Fund, the Prostate Cancer Foundation and the German-Israel Foundation. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yosef Yarden.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

FURTHER INFORMATION

RTK consortium

Alliance for Cell Signaling (AFCS)

Signal Transduction Knowledge Environment (STKE)

Institute for Systems Biology

Systems Biology Markup Language (SBML)

BioModels

Glossary

Receptor tyrosine kinase

Transmembrane receptor with an intrinsic ability to transfer phosphate groups to tyrosine residues contained in cellular substrates.

Heterodimeric

In contrast to a homodimer, in which two identical receptors bind to form a dimer, heterodimers are formed by two different receptors.

Mitogen activated protein kinase

(MAPK). Parallel kinase cascades lead to the activation of the four serine/threonine MAPKs (ERK, JNK, p38 and ERK5/BMK). Activation of these kinases is critical to cellular signal transduction, driving diverse cell fates.

Phosphatidylinositol 3-kinase

(PI3K). A lipid kinase, that is the initiating enzyme in a pathway that promotes cell proliferation and survival. A central downstream mediator of the pathway is the serine/threonine kinase AKT/PKB. PI3K phosphorylates the 3′ position of the inositol ring of phosphatidylinositol-4,5-bisphosphate.

Autocrine

Secretion of a ligand that stimulates the secreting cell itself.

Waved-1 and waved-2 mice

Naturally occurring mutant mice that have wavy hair. In waved-1 mice, TGFα levels are reduced, whereas waved-2 mice have a partial inactivation of the kinase domain of ERBB1, owing to a point mutation.

Endocytosis

The process of taking in materials from outside a cell in vesicles that arise by the inward folding ('invagination') of the plasma membrane.

Trabeculae

Finger-like extensions of the ventricular myocardium.

Giant strong component network (or core process)

The largest fully connected part of a network, which functions as the core of the network, and is normally the most complicated part of the network.

Evolvability

The capacity of an organism to generate heritable phenotypic variance.

Paracrine

Activation of a receptor on an adjacent cell by a secreted ligand.

Heat shock protein-90

(HSP90). A molecular chaperone that buffers the conformation and activity of a distinct subset of cellular molecules that are involved in signal transduction. HSP90 is one of the most abundant cellular proteins.

Caveolae

Cholesterol-rich membrane microdomains that are stabilized by the protein caveolin.

Clathrin-coated vesicles

Specialized vehicles of internalization from the plasma membrane, coated with a polyhedral lattice of the protein clathrin.

Emergent behaviour

Complex behaviour that cannot be predicted from the properties of system components in isolation, but only emerges when the components are put together in a functional whole.

Psoriasis

A chronic skin disorder of genetic origin that is caused by inflammation-driven hyperproliferation of epidermal cells. Appears as red, scaly elevated plaques, specifically on joints.

Atherosclerosis

A progressive disease of the arterial blood vessel. It is caused by the formation of plaques that cause narrowing and hardening of the arteries, reducing blood flow to the heart.

Bistability

Defines that the system will transit between two states, 'on' and 'off', with no, or little, intermediary states.

Network fragility

As a network evolves robustness to particular changes, this necessarily entails an increase in its vulnerability to perturbations from unexpected sources, defining its points of fragility.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Citri, A., Yarden, Y. EGF–ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7, 505–516 (2006). https://doi.org/10.1038/nrm1962

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1962

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing