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和刺激细胞生长。先前的研究已经表明，交换a1和β 1的胞质结构域导致整合素具有缺陷的信号传导，尽管它具有结合配体的能力。β亚基的胞质结构域内的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转导后跨膜构象变化的机制。第二个目标将比较野生型和缺陷型受体，以剖析通过FAK的信号传导的近端方面。在缺陷受体中，FAK被激活，但嵌合受体不磷酸化CAS。研究将集中在cSrc及其介导FAK和CAS之间信号传导的能力。将表达cSrc的突变形式以确定它们是否将拯救缺陷受体。第三个目标将集中在通过适配器Shc的a1b1生长信号。在Jurkat细胞中的研究发现，与成纤维细胞相反，在这些细胞中需要受体酪氨酸磷酸酶CD 45和Src激酶Lck，并且Src激酶Fyn是不足的。研究将解决Src激活和Shc信号传导的机制。最后，研究将使用两种胶原蛋白受体a1b1和a2b1来解决上述生长信号的后果，这两种胶原蛋白受体在磷酸化Shc的能力上不同。该系统将用于检查与肽生长因子受体信号协同作用中所涉及的整合素信号的性质。

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.