A Novel Substrate of Src Tyrosine Kinases

描述（由申请人提供）：Fyn酪氨酸激酶， Src家族促进角质形成细胞分化。角质形成细胞免受 Fyn缺陷小鼠表现出鳞状细胞形成受损， 分化标志物如聚丝蛋白和转氨酶的表达。 此外，Fyn缺乏的角质形成细胞显示出减少的酪氨酸磷酸化， 连环蛋白是正常细胞间粘附所必需的。理解 Fyn如何诱导角质形成细胞分化据说是 在分子水平上了解皮肤病。他们假设菲恩 可以通过与其他分子相互作用并使其磷酸化来发挥其作用。 为了解决这个问题，他们对小鼠进行了酵母双杂交筛选， 使用Fyn作为诱饵构建角质形成细胞文库。这个屏幕产生了一部小说 被Fyn磷酸化并与Fyn缔合的推定接头分子; 他们称这种分子为Srcasm：Src激活和信号分子。他们 建议对Fyn和Srcasm之间的相互作用进行生物化学表征 并阐明Srcasm中的哪些残基是Fyn磷酸化所必需的， 协会他们还将研究Srcasm如何与其他信号联系起来 分子，并表征Srcasm在上皮细胞和人类中的表达 皮肤病随着腺病毒产生各种形式的Fyn和Src， 他们将评估Srcasm在以下信号转导途径中的作用： 这些原代角质形成细胞内的激酶。最后，由于他们在 原位研究，他们将Srcasm的表达靶向部分表皮 以及毛囊中没有表达的部分，并将检查 异常Srcasm表达。 本申请为指导临床科学家发展奖是 设想促进候选人从博士后过渡到 独立调查员候选人将投入85%的精力进行研究 旨在表征一种新的Src家族激酶底物在 角质形成细胞信号转导这项研究将在该部门进行 一家大型教学医院的皮肤科， 并致力于医生科学家的专业发展。的 申请人剩下的工作，15%，将涉及诊断皮肤活检。

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.