STRUCTURE/FUNCTION OF THE INTEGRIN ALPHA 1 BETA 1

描述(摘自申请人的摘要)：本更新提案的主要目标是确定整合素a1b1的细胞内信号的机制和结果。在与配体结合时，该受体产生多种信号，这些信号组织肌动蛋白细胞骨架并刺激细胞生长。先前的研究表明，尽管整合素具有结合配体的能力，但交换A1和Beta1的细胞质结构域会导致整合素信号的缺陷。在β亚基的细胞质区域内插入可以恢复该受体的信号特性。该模型将被用来研究信号转导发生跨膜构象变化的机制。第二个目标将比较野生型和缺陷受体，以剖析FAK信号的近端方面。在有缺陷的受体中，FAK被激活，但嵌合受体不会使CAS磷酸化。研究将集中在中国证监会及其在FAK和CAS之间调解信号的能力。中国证监会将表达突变形式，以确定它们是否会拯救有缺陷的受体。第三个目标将专注于通过适配器Shc发出的a1b1生长信号。在Jurkat细胞中的研究发现，与成纤维细胞相比，受体酪氨酸磷酸酶CD45和Src激酶Lck是必需的，而Src激酶Fyn在这些细胞中是不够的。研究将探讨Src激活和Shc信号转导的机制。最后，研究将使用两种胶原蛋白受体a1b1和a2b1来研究上述生长信号的后果，这两种胶原蛋白受体对Shc的磷酸化能力不同。该系统将用于检测整合素信号与多肽生长因子受体信号协同作用的性质。

DESCRIPTION (Adpated from applicant's abstract): The primary goal of this renewal proposal is to determine the mechanism and consequences of intracellular signals from the integrin a1b1. Upon ligand binding, this receptor produces multiple signals which organize the actin cytoskeleton and stimulant cell growth. Previous studies have shown that swapping the cytoplasmic domains of a1 and beta1 leads to an integrin with defective signaling despite its capacity to bind ligand. An insertion within the cytoplasmic domain of the beta subunit can restore the signaling properties of this receptor. This model will be used to study the mechanism of the transmembrane conformation change occurring upon signaling. The second aim will compare wild type and defective receptors to dissect the proximal aspects of signaling via FAK. In the defective receptor FAK is activated yet the chimeric receptor does not phosphorylate CAS. Studies will focus upon cSrc and its ability to mediate the signaling between FAK and CAS. Mutant forms of cSrc will be expressed to determine if they will rescue the defective receptors. The third aim will focus on a1b1 growth signals through the adaptor Shc. Studies in Jurkat cells found that the receptor tyrosine phosphatase CD45 and the Src kinase Lck are required and the Src kinase Fyn is not sufficient in the these cells, in contrast to fibroblasts. Studies will address the mechanism of Src activation and Shc signaling. Finally, studies will address the consequences of the above mentioned growth signals using the two collagen receptors a1b1 and a2b1, which differ in their ability to phosphorylate Shc. This system will be use to examine the nature of integrin signals involved in the synergy with peptide growth factor receptor signals.