PathFinder Cell Signaling Pathway

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EGF Pathway Map
Copyright ©2006 ProteinLounge.com

 EGF Pathway

The epidermal growth factor (EGF) family consists of four related receptors: EGFR (EGFR1) (ErbB1); ErbB2 (Neu, HER2); ErbB3 (HER3); and ErbB4 (HER4) which are variously activated by EGF, TGFa, amphiregulin (SDGF), betacellulin (BTC), epiregulin (EREG), heparin-binding EGF-like growth factor (HB-EGF) and the neuregulins (NRG1, NRG2, NRG3 and NRG4). Ligand-activated EGF receptors form homo- and hetero-dimers that contain tyrosine kinase (TR) activity. Individual and specific EGF/neuregulin receptor monomeric proteins contribute to the ligand and response specificity of the EGFR dimer and initiate multiple distinct signaling pathways.

EGF receptors typically promote cell survival, growth and differentiation via the activation of several integrated signaling pathways. These frequently involve the early activation of the key upstream signaling elements: phospholipase C; PI3K; Ras-GTPase and Src kinase. EGFR binds phospholipase C-g1 through its SH2 domain and activates this lipase through phosphorylation. Activation of PLC-g1 leads to the formation of IP3 and diacylglycerol. PIP3 induces the release of the second messenger calcium from the ER, which together with DAG activates various conventional and novel protein kinase Cs. Activation of phosphatidylinositol-3-kinase (PI3K) results in the activation of the PDK1; Akt/PKB pathway. Phosphorylated EGFR binds the Grb2:SOS complex which activates the p21Ras-GTPase pathway leading to ERK activation. Src kinase can be linked to EGFR through adaptor proteins p66Shc and p52Shc. STAT (signal transducers and activators of transcription factors) proteins (STAT1, STAT3 and STAT5) can be differentially activated directly by the EGFR tyrosine kinase and/or associated Src kinase. The integration and mitigation of these signaling pathways contribute to the final cell response to EGFR agonists.

References:

  1. Carpenter, G. and Ji, Q. (1999) Phospholipase C-gamma as a signal-transducing element. Exp. Cell Res. 253, 15-24.

  2. Garcia, R. et. al. (2001) Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20, 2499-2513.

  3. Henson, E. S. and Gibson, S. B. (2006) Surviving cell death through epidermal growth factor (EGF) signal transduction pathways: Implications for cancer therapy. Cell Signal. 2006 May 24

  4. Olayioye, M. A. et. al. (1999) ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases. J. Biol. Chem. 274, 17209-17218.

  5. Guren, T. K. et. al. (2003) EGF receptor-mediated, c-Src-dependent, activation of Stat5b is down regulated in mitogenically responsive hepatocytes. J. Cell Physiol. 196, 113-123.

  6. Sato, K. et. al. (2002) Adaptor protein Shc is an isoform-specific direct activator of the tyrosine kinase c-Src. J. Biol. Chem. 277, 29568-29576.


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Content for this page is provided by Dennis R. Conrad, Ph.D., a Life Science industry consultant with over 25 years of experience in the formulation and optimization of cell culture media. Dr. Conrad's email address is biomediaexpert@earthlink.net