The role of srcasm in keratinocyte biology

srcasm 在角质形成细胞生物学中的作用

• 批准号: 7870731
• 负责人: John T. Seykora
• 金额: $ 1.37万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-14 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870731
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adhesions; Affect; American; Binding Sites; Biology; C-terminal; Cell Proliferation; Cells; Characteristics; Cutaneous; Data; Development; EGF gene; Epidermal Growth Factor Receptor; Epidermis; Epithelial; Equilibrium; Goals; Grant; Growth; Growth Factor; Homeostasis; Hyperplasia; Inflammatory; Investigation; Knowledge; Ligands; Link; Mitogen-Activated Protein Kinases; Molecular; Neoplasms; Pathway interactions; Phase; Phosphorylation; Phosphotransferases; Platelet-Derived Growth Factor; Play; Process; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Regulatory Pathway; Research Proposals; Role; SH3 Domains; Signal Pathway; Signal Transduction; Signaling Molecule; Societies; Structure; Transgenic Mice; Transgenic Organisms; Tyrosine; Tyrosine Phosphorylation; Work; base; cell type; extracellular; in vivo; insight; keratin 5; keratinocyte; keratinocyte differentiation; mutant; neoplastic; novel; overexpression; poly(L-glutamic acid(60)-L-alanine(30)-L-tyrosine(10)); skin disorder; src-Family Kinases

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.

描述（申请人提供）：表皮稳态对维持表皮的功能至关重要，它依赖于角质形成细胞增殖和脱落鳞片之间的平衡。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皮肤疾病是重要的，这些疾病影响着美国社会的大部分。

项目成果

Keratin 15-positive stem cells give rise to basal cell carcinomas in irradiated Ptch1(+/-) mice.

角蛋白 15 阳性干细胞在受辐射的 Ptch1(/-) 小鼠中产生基底细胞癌。

• DOI: 10.1016/j.ccr.2011.01.006
• 发表时间: 2011
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Seykora,JohnT;Cotsarelis,George
• 通讯作者: Cotsarelis,George