STRUCTURE/FUNCTION OF THE INTEGRIN ALPHA 1 BETA 1

整合素 ALPHA 1 BETA 1 的结构/功能

• 批准号: 6386004
• 负责人: EUGENE E. MARCANTONIO
• 金额: $ 36.29万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6386004
• 关键词: 3T3 cells; biological signal transduction; cell cell interaction; cell migration; chimeric proteins; clone cells; collagen; conformation; extracellular matrix; growth factor receptors; integrins; mitogen activated protein kinase; phosphorylation; protein structure function; protooncogene; receptor binding; receptor expression; site directed mutagenesis

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.

描述（根据申请人的摘要拟合）：该更新建议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，该受体会产生多个信号，这些信号组织肌动蛋白细胞骨架和刺激性细胞生长。先前的研究表明，尽管具有结合配体的能力，但交换A1和BetA1的细胞质结构域仍导致具有缺陷的信号素。 β亚基的细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传导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有缺陷的受体，以通过FAK剖析信号传导的近端方面。在有缺陷的受体FAK中被激活，但嵌合受体不磷酸化Cas。研究将侧重于CSRC及其介导FAK和CAS之间的信号传导的能力。将表达CSRC的突变形式，以确定它们是否会挽救缺陷的受体。第三个目标将通过适配器SHC集中在A1B1增长信号上。在Jurkat细胞中的研究发现，与成纤维细胞相比，这些细胞中需要受体酪氨酸磷酸酶CD45和SRC激酶LCK，而SRC激酶FYN在这些细胞中不够。研究将解决SRC激活和SHC信号传导的机制。最后，研究将使用两个胶原受体A1B1和A2B1来解决上述生长信号的后果，这些胶原受体的磷酸化SHC能力有所不同。该系统将用于检查与肽生长因子受体信号协同作用的整合素信号的性质。