Epidermal homeostasis is critical for maintaining a functional epidermis, and it relies on a balance between keratinocyte proliferation and the squames that are shed. Critical components in maintaining this balance are the molecular mechanisms by which keratinocytes integrate growth regulatory signals in a coherent manner to provide a balance between cellular proliferation and differentiation. Although some of the molecular mechanisms for regulating keratinocyte proliferation and differentiation have been characterized, further work is needed to understand these key signaling pathways. Studies that delineate the molecular mechanisms of keratinocyte proliferation and differentiation are important for understanding epidermal homeostasis (function) and a wide range of inflammatory and neoplastic cutaneous disorders, that affect large segments of American society. Intracellular tyrosine kinases are critical for regulating cellular proliferation and differentiation. The highly conserved Src-family of tyrosine kinases (SFKs) are ubiquitously expressed, non-receptor tyrosine kinases that play important roles in cellular proliferation and differentiation. It is known that SFKs play a role in regulating keratinocyte proliferation and differentiation. Therefore, it is of import to better understand how SFKs are regulated in keratinocytes. An important insight into the intracellular regulation of SFKs came with the recent discovery of Srcasm (Src-activating and signaling molecule). Srcasm modulates SFKs and associate with important signaling molecules such as Grb2 and PI-3 kinase; both TGF-a and EGF promote tyrosine phosphorylation of Srcasm. Srcasm can regulate the activity of the p44/42 MAP kinases based on the level of EGF receptor signaling. Srcasm can either stimulate or downregulate signals from the EGFR depending on the cellular context. Increased Srcasm levels are associated with decreased keratinocyte proliferation and increased differentiation. Srcasm levels are decreased in cutaneous neoplasia, and increased Srcasm expression can correct the hyperproliferative epidermis seen in transgenic mice overexpressing Fyn. This proposal will characterize the role of Srcasm in keratinocyte biology by studying its role in regulating growth factor-dependent signaling, proliferation, and differentiation. This work will determine which portions of Srcasm are important for activating and down-regulating signaling through the EGFR-SFK-MAP kinase pathway. The in vivo effects of SFKs and Srcasm on epidermal development and function will be determined by characterizing double transgenic strains over-expressing SFKs and Srcasm.
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