Our growth regulation research has been concerned with oncogenes and tumor suppressor genes as positive and negative regulators of normal and neoplastic growth. We have studied the Ras-specific guanine nucleotide exchange factors (Ras-GNEFs), which play a key role in signal transduction, and in activation of the ras proto-oncogene. Most recently, we have begun to investigate E-cadherin, a key cell surface adhesion protein that is a tumor suppressor that is frequently silenced in many epithelial cancers and melanoma. We have found that E-cadherin specifically inhibits the activation of a variety of receptor tyrosine kinases (RTKs) by their physiologic ligands. The inhibition probably results from the formation of a complex between E-cadherin and the RTKs, which restricts the ability of the ligands to bind their cognate RTK with high affinity. This inhibitory activity of E-cadherin is abrogated when it is silenced in tumors, permitting more robust responses to RTKs by their ligands, a widespread phenomemon implicated in the pathogenesis of many tumors. Future studies will examine other mechanisms by which E-cadherin regulates cell growth and the possibility of using E-cadherin as a potential cancer treatment target.
