A Novel Substrate of Src Tyrosine Kinases

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DESCRIPTION (provided by the applicant): The Fyn tyrosine kinase, a member of the Src family, promotes keratinocyte differentiation. Keratinocytes from Fyn-deficient mice exhibit impaired squame formation, and markedly decreased expression of differentiation markers such as filaggrin and transglutaminase. Also, Fyn-deficient keratinocytes show decreased tyrosine phosphorylation of catenins which are necessary for proper intercellular adhesion. Understanding how Fyn induces keratinocyte differentiation is said to be fundamental for understanding cutaneous disease at a molecular level. They hypothesize that Fyn may exert its effects by interacting with and phosphorylating other molecules. To address this question, they performed a yeast two-hybrid screen of a murine keratinocyte library using Fyn as the bait. This screen yielded a novel putative adaptor molecule which is phosphorylated by and associates with Fyn; they term this molecule Srcasm: Src activating and signaling molecule. They propose to biochemically characterize the interaction between Fyn and Srcasm and elucidate what residues in Srcasm are required for Fyn phosphorylation and association. They will also examine how Srcasm associates with other signaling molecules and characterize the expression of Srcasm in epithelial and human cutaneous diseases. With adenoviruses producing various forms of Fyn and Src, they will evaluate the role of Srcasm in the signal-transduction pathways of these kinases within primary keratinocytes. Lastly, as a result of their in situ studies, they will target expression of Srcasm to parts of the epidermis and hair follicle where it is not expressed and will examine the effects of aberrant Srcasm expression. This application for a Mentored Clinical Scientist Development Award is envisaged to promote the candidate's transition from a postdoctoral fellow to an independent investigator. The candidate will devote 85% effort to research designed to characterize the role of a novel Src family kinase substrate in keratinocyte signal transduction. The research will be done in the Department of Dermatology of a major teaching hospital which has a supportive environment and a commitment to the professional development of physician scientists. The rest of the applicant's effort, 15%, will involve diagnosing skin biopsies.