STRUCTURE/FUNCTION OF THE INTEGRIN ALPHA 1 BETA 1

描述（改编自申请人摘要）：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后果。配体结合后，该受体产生多种信号，组织肌动蛋白细胞骨架，促进细胞生长。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β a1的细胞质结构域会导致信号传导缺陷。在β亚基的细胞质区域内插入可以恢复该受体的信号传导特性。该模型将用于研究信号传递时发生的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，剖析通过FAK信号传导的近端方面。在缺陷受体中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调解FAK和CAS之间信号的能力。将表达cSrc的突变形式，以确定它们是否会挽救有缺陷的受体。第三个目标将集中于通过适配器Shc的a1b1生长信号。对Jurkat细胞的研究发现，与成纤维细胞不同，Jurkat细胞需要酪氨酸磷酸酶受体CD45和Src激酶Lck，而Src激酶Fyn不充足。研究将探讨Src激活和Shc信号传导的机制。最后，研究将利用两种胶原受体a1b1和a2b1来解决上述生长信号的后果，这两种胶原受体磷酸化Shc的能力不同。该系统将用于研究整合素信号与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.