EGF Receptor Signal Transduction Pathway

The epidermal growth factor (EGF) family of receptor tyrosine kinases consists of four receptors, EGF-R (ErbB1), ErbB2 (Neu), ErbB3, and ErbB4. Members of the EGF-R family contain a cytoplasmic tyrosine kinase domain, a single transmembrane domain, and an extracellular domain that is involved in ligand binding and receptor dimerization. Activation of the EGF-R results in the initiation of a diverse array of cellular pathways. In response to toxic environmental stimuli, such as ultraviolet irradiation, or to receptor occupation by EGF, the EGF-R forms homo- or heterodimers with other family members. Each dimeric receptor complex will initiate a distinct signaling pathway by recruiting different Src homology 2 (SH2)-containing effector proteins. Dimerization results in autophosphorylation initiating a downstream cascade of events culminating in cellular responses such as cell proliferation or apoptosis. The activated EGF-R dimer complexes with the adapter protein, Grb, coupled to the guanine nucleotide releasing factor, SOS. The Grb-SOS complex can either bind directly to phosphotyrosine sites in the receptor or indirectly through Shc. These protein interactions bring SOS in close proximity to Ras, allowing for Ras activation This subsequently activates the ERK and JNK signaling pathways that, in turn, activate transcription factors, such as c-fos, AP-1, and Elk-1, that promote gene expression and contribute to cell proliferation.

Back to Top

References:

Daly, R.J., Take your partners, please - signal diversification by the erbB family of receptor tyrosine kinases. Growth Factors, 16, 255-263 (1999).

Wells, A., EGF receptor. Int. J. Biochem. Cell Biol., 31, 637-643 (1999).

Rosette, C., Karin, M., Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. Science, 274, 1194-1197 (1996).

Qian, X., et al., N terminus of Sos1 Ras exchange factor: critical roles for the Dbl and pleckstrin homology domains. Mol. Cell Biol., 18, 771-778 (1998).