Receptor tyrosine kinases, including the epidermal growth factor (EGF) receptor, are important regulators of diverse cellular functions such as cell proliferation, differentiation, morphogenesis and motility. Disruptions in the EGF receptor signal transduction pathway are frequently detected in squamous cell carcinoma (SCC) and appear to play an important role in the pathogenesis of oral cancers. Many oral SCCs disply regional recurrence or metastatic behavior, and based on the involvement of the EGF receptor in the invasive behavior of other tumors, we propose that EGF receptor overexpression may contribute to the progression toward an invasive phenotype in oral SCC. The EGF receptor is the best characterized member of the erbB family of receptor tyrosine kinases, which also includes the closely related erbB2, erbB3 and erbB4 receptors. The erbB receptors form functional ligand dependent homo- and hetero-dimeric complexes which provides signaling diversity within this subfamily of receptor tyrosine kinases. Based on: 1) the functional interactions and heterologous phosphorylation between erbB receptors in signal transduction, 2) co-expression of the EGF receptor, erbB2 and erbB3 in keratinocytes, 3) the observation that overexpression of erbB3 in oral SCC is associated with lymph node metastasis, and 4) our studies demonstrating that EGF receptor overexpression promotes SCC cell motility, this proposal will address potential interrelationships between the EGF receptor and other erbB family members in generating a migratory and invasive phenotype in SCC. In particular, we will investigate potential changes in cross-talk between erbB family members and regulation of key signal transduction pathways as a consequence of receptor overexpression. We hypothesize that the EGF receptor is essential for biological responses associated with SCC tumor cell invasion through either a direct mechanism, or EGF receptor mediated activation of other erbB receptors.
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