Regulation of FAK Signaling in Mammary Epithelial Cells by Cbl Proto- oncogene Product

摘要

Proliferation and differentiation of breast epithelial cells are regulated by the coordinated activation of the cellular tyrosine kinase machinery upon stimulation through growth factor receptors and extra-cellular matrix receptor-induced activation of focal adhesion kinase FAK. This proposal is designed to investigate a novel hypothesis that Cbl, a negative regulator of growth factor receptors, attenuates FAK-dependent growth signals in mammary epithelial cells. For this purpose, the Cbl interaction sites on FAK will be determined and the impact of mutations in these sites on the ability of FAK to mediate growth signals will be investigated. Given the recent findings that Cbl functions as an ubiquitin ligase towards tyrosine kinases, we are examining the possibility that Cbl regulates FAK signaling by targeting FAK or its signaling substrates for degradation. The work reported here describes initial characterization of FAK mutants that appear to be unable to interact with Cbl tyrosine kinase-binding domain. Together with mutant forms of Cbl that do not mediate ubiquitination, these studies will establish if FAK is a target of Cbl. The present studies, thus, aim to define novel strategies to down-regulate proliferation signals in breast cancer cells.