FAK family tyrosine kinases and Rho family GTPases

FAK 家族酪氨酸激酶和 Rho 家族 GTP 酶

基本信息

批准号：
6624426
负责人：
WEN-CHENG XIONG
金额：
$ 23.93万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2007-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6624426
关键词：
biological signal transduction cell cell interaction cell line cell migration cytoskeleton extracellular matrix focal adhesion kinase gene mutation guanine nucleotide binding protein guanosinetriphosphatases integrins intermolecular interaction molecular site phosphorylation posttranslational modifications protein structure function protein tyrosine kinase

项目摘要

DESCRIPTION (provided by applicant): Cell adhesion to extracellular matrix (ECM) initiates multiple signaling cascades including activation of focal adhesion kinase (FAK) family kinases and Rho family GTPases that regulate the organization of actin cytoskeleton and changes in gene expression. Rho family GTPases, particularly Rho, Rac, and CDC42, have emerged as central coordinators of a variety of cellular processes including actin cytoskeletal organization. FAK family kinases including FAK and proline-rich tyrosine kinase 2 (PYK2) play important roles in regulating cell migration. The mechanisms by which PYK2 and FAK participate in and regulate actin cytoskeletal organization remain largely unknown. How FAK family kinases cross talk with Rho family GlPases to coordinately organize the complex signaling required for actin cytoskeletal organization and cell migration is a central question of this proposal. In preliminary studies, we found that PYK2 and FAK are upstream regulators of CDC42 and RhoA. Using yeast two-hybrid system, we identified a novel PYK2 and FAK interacting protein, PSGAP (for PH domain and SH3 domain containing RhoGAP protein), which may be a crucial signaling protein for PYK2 and FAK to cross talk with Rho family proteins. Based on these preliminary results, we hypothesize that PYK2 and FAK regulate Rho family GTPases via PSGAP, to organize actin cytoskeleton and to modulate cell migration. To test this hypothesis, we will: 1) determine the role of PSGAP in integrin- or FAK-mediated transient inactivation of Rho, cell spreading, and cell migration; 2) determine the role of PSGAP in integrin- or PYK2-mediated activation of CDC42 and actin cytoskeletal reorganization; 3) investigate the mechanisms by which PSGAP is regulated. The proposed research will start to piece together a signaling pathway by which FAK and PYK2 coordinately regulate actin cytoskeletal organization and cell migration. The resulting data will provide insight into mechanisms by which integrin regulates cell adhesion and migration. Such knowledge is essential for understanding the mechanisms involved in abnormal adhesion that leads to pathological states, such as tumor metastasis.

描述（由申请人提供）：细胞粘附到细胞外基质 (ECM) 启动多个信号级联，包括激活局部粘附激酶 (FAK) 家族激酶和 Rho 家族 GTP 酶调节肌动蛋白细胞骨架的组织和基因表达的变化。罗氏家族 GTPases，特别是 Rho、Rac 和 CDC42，已成为中央协调员包括肌动蛋白细胞骨架组织在内的多种细胞过程。 FAK 家族激酶包括 FAK 和富含脯氨酸的酪氨酸激酶 2 (PYK2) 在调节细胞迁移中发挥重要作用。 PYK2 和 FAK 在很大程度上参与和调节肌动蛋白细胞骨架组织未知。 FAK 家族激酶如何与 Rho 家族 GlPases 相互作用协调组织肌动蛋白细胞骨架所需的复杂信号传导组织和细胞迁移是该提案的核心问题。在初步研究中，我们发现PYK2和FAK是上游调节因子 CDC42 和 RhoA。使用酵母双杂交系统，我们鉴定了一种新型 PYK2 和 FAK 相互作用蛋白，PSGAP（针对包含 RhoGAP 的 PH 结构域和 SH3 结构域）蛋白），这可能是 PYK2 和 FAK 交叉的关键信号蛋白与 Rho 家族蛋白质交谈。根据这些初步结果，我们假设 PYK2 和 FAK 通过 PSGAP 调节 Rho 家族 GTPases，以组织肌动蛋白细胞骨架并调节细胞迁移。为了测试这个假设，我们将：1）确定 PSGAP 在整合素或整合素中的作用 FAK 介导的 Rho 瞬时失活、细胞扩散和细胞迁移； 2) 确定 PSGAP 在整合素或 PYK2 介导的激活中的作用 CDC42和肌动蛋白细胞骨架重组； 3）研究机制 PSGAP 受到监管。拟议的研究将开始拼凑一条信号通路，通过该通路 FAK和PYK2协调调节肌动蛋白细胞骨架组织和细胞迁移。由此产生的数据将提供对机制的深入了解整合素调节细胞粘附和迁移。这些知识对于了解导致异常粘附的机制病理状态，例如肿瘤转移。