Signaling pathways and effects of EGFR

Signaling pathways and effects of EGFR. Upon binding to one of multiple ligands, EGFR dimerizes with another member of the EGFR family, leading to the activation of the TK domain, phosphorylation of critical tyrosine residues in the EGFR intracellular domain, and activation of downstream signaling pathways, including MAPK, JAK-STAT, PLC, and PI3K–Akt. Collectively, EGFR signaling may lead to increased cell proliferation, decreased apoptosis, increased angiogenesis, increased invasion, and increased metastasis. As depicted above, multiple opportunities exist to inhibit EGFR signaling; for example, monoclonal antibodies (e.g., cetuximab and panitumumab) interact with the extracellular domain of EGFR preventing ligand-induced activation of the receptor, and small-molecule inhibitors (e.g., gefitinib, erlotinib, and lapatinib) block activation of the TK domain preventing induction of EGFR signaling pathways. Specific EGFR mutations may lead to constitutive activation of EGFR regardless of ligand binding and/or resistance of EGFR to the effects of TK inhibitors. Independent of receptor status, EGFR downstream signaling may become aberrantly activated; for example, mutant Ras may lead to constitutive activation of the MAPK pathway or mutation/loss of PTEN may lead to loss of negative regulation of the PI3K–Akt pathway.Abbreviations: DAG, diacylglycerol; EGFR, epidermal growth factor receptor; IP3, inositol triphosphate; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/extracellular signal–related kinase kinase; PDK, 3-phosphoinositide-dependent protein kinase; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PTEN, phosphatase and tensin homologue deleted on chromosome ten; STAT, signal transducer and activator of transcription; TGF, transforming growth factor; TK, tyrosine kinase.

Publication

Treatment of Unresectable and Metastatic Cutaneous Squamous Cell Carcinoma. (2010) Lee D. Cranmer, et al. Oncologist. 2010 Dec;15(12):1320-1328. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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