The role of srcasm in keratinocyte biology

描述(申请人提供)：表皮动态平衡是维持功能性表皮的关键，它依赖于角质形成细胞增殖和脱落的鳞片之间的平衡。维持这种平衡的关键成分是角质形成细胞以一致的方式整合生长调节信号以在细胞增殖和分化之间提供平衡的分子机制。尽管一些调控角质形成细胞增殖和分化的分子机制已经确定，但还需要进一步的工作来了解这些关键的信号通路。研究角质形成细胞增殖和分化的分子机制，对于了解表皮的动态平衡和广泛的炎症性和肿瘤性皮肤病是很重要的，这些疾病影响了美国社会的大部分人。 细胞内酪氨酸激酶是调节细胞增殖和分化的关键。高度保守的酪氨酸激酶(SFK)家族是广泛表达的非受体酪氨酸激酶，在细胞增殖和分化中发挥重要作用。已知SFK对角质形成细胞的增殖和分化具有调节作用。因此，更好地了解SFK是如何在角质形成细胞中被调控的具有重要意义。 最近发现了srCasm(src激活和信号分子)，这是对sFKs细胞内调控的一个重要见解。SrCasm调控sFKs，并与Grb2、PI-3等重要信号分子结合，转化生长因子-α和表皮生长因子均促进srCasm的酪氨酸磷酸化。SRCasm可通过调节EGF受体信号水平来调节p44/42 MAP激酶的活性。SRCasm可以刺激或下调EGFR的信号，这取决于细胞环境。SRCasm水平升高与角质形成细胞增殖减少和分化增加有关。在皮肤肿瘤中，srCasm水平降低，并且srCasm表达增加可以纠正过度表达Fyn的转基因小鼠的过度增殖的表皮。 这项建议将通过研究sRCasm在调节生长因子依赖的信号、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。这项工作将确定通过EGFR-SFK-MAP激酶途径激活和下调信号的SRCasm的哪些部分是重要的。SFKs和srCasm在体内对表皮发育和功能的影响将通过鉴定过量表达sFKs和srCasm的双转基因菌株来确定。

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.