The role of srcasm in keratinocyte biology

描述（由申请人提供）：表皮稳态对于维持功能性表皮至关重要，并且它依赖于角质形成细胞增殖和脱落的鳞状细胞之间的平衡。维持这种平衡的关键组成部分是角质形成细胞以连贯的方式整合生长调节信号以提供细胞增殖和分化之间的平衡的分子机制。虽然一些调节角质形成细胞增殖和分化的分子机制已经被表征，但需要进一步的工作来理解这些关键的信号通路。描述角质形成细胞增殖和分化的分子机制的研究对于理解表皮稳态（功能）和广泛的炎症和肿瘤性皮肤疾病是重要的，这些疾病影响着美国社会的大部分人群。 细胞内酪氨酸激酶对于调节细胞增殖和分化至关重要。Src家族酪氨酸激酶（SFKs）是一类广泛表达的非受体酪氨酸激酶，在细胞增殖和分化中起重要作用。已知SFKs在调节角质形成细胞增殖和分化中起作用。因此，更好地了解SFKs在角质形成细胞中的调节是重要的。 最近Srcasm（Src激活和信号分子）的发现对SFKs的细胞内调节有了重要的认识。Srcasm调节SFK并与重要的信号分子如Grb 2和PI-3激酶相关; TGF-α和EGF均促进Srcasm的酪氨酸磷酸化。Srcasm可根据EGF受体信号水平调节p44/42 MAP激酶的活性。Srcasm可以刺激或下调来自EGFR的信号，这取决于细胞环境。Srcasm水平增加与角质形成细胞增殖减少和分化增加相关。Srcasm水平在皮肤肿瘤中降低，并且Srcasm表达增加可以纠正在过表达Fyn的转基因小鼠中看到的过度增殖的表皮。 该提案将通过研究Srcasm在调节生长因子依赖性信号传导、增殖和分化中的作用来表征Srcasm在角质形成细胞生物学中的作用。这项工作将确定Srcasm的哪些部分对于通过EGFR-SFK-MAP激酶途径激活和下调信号传导是重要的。将通过表征过表达SFKs和Srcasm的双转基因菌株来确定SFKs和Srcasm对表皮发育和功能的体内作用。

DESCRIPTION (provided by applicant): 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.