P21-activated kinases in cell-cell and cell-matrix adhesion signaling

P21激活的细胞-细胞和细胞-基质黏附信号通路 摘要 多细胞生物体的发育和功能、组织的形成和对伤害和 感染依赖于细胞之间以及细胞与细胞外基质之间紧密协调的黏附。 这些过程在很大程度上是通过两个黏附受体家族的作用来调节的：整合素 它们主要负责细胞-基质的黏附，以及对细胞-细胞起中心作用的钙粘附素 粘附力。我们的初步数据表明，II型p21激活的激酶(PAKs)，一组丝氨酸-2激活的蛋白- 苏氨酸激酶使用一系列机制来影响细胞-基质黏附和细胞-细胞黏附。这个 调节两种黏附系统的能力使PAK成为协调细胞黏附的中心参与者 动力学。这项建议旨在了解这一调控的功能、细胞和分子基础。至 解决它们如何控制细胞-基质和细胞-细胞黏附的问题我们提出了结构、生化 和蜂窝方法。在目标1中，我们检验了PAK与整合素的细胞质尾巴直接结合的假设 黏附受体调节基质黏附和/或PAK信号。我们将进行广泛的研究 采用结构、生物物理、生化和细胞生物学方法。这将使我们能够 全面了解整合素黏附受体如何与PAK丝氨酸-苏氨酸激酶结合，以及 这种相互作用对细胞信号、黏附、运动和侵袭的功能后果。在目标2中，我们测试 假设以细胞-细胞接触为靶点的PAK使b-连环蛋白磷酸化，触发黏附转换和 单个细胞从上皮岛逃逸。我们将确定PAK驱赶殖民地的机制 逃逸，以及PAK调控β-连环蛋白的结构基础。最后，我们将测试PAK的角色是否 细胞间黏附和细胞间ECM黏附是联系在一起的。我们提议的工作将定义PAK如何调节整合素- 介导的细胞-基质黏附，以及β-连环蛋白相关的细胞-细胞黏附，因此将提供新的 通过II型PAK了解细胞-基质和细胞-细胞黏附之间的相互联系。

P21-activated kinases in cell-cell and cell-matrix adhesion signaling ABSTRACT The development and functioning of multicellular organisms, tissue formation, and responses to injury and infection rely on tightly coordinated adhesion of cells to one another, and of cells to the extracellular matrix. These processes are mediated in large part through the action of two families of adhesion receptors: the integrins which are principally responsible for cell-matrix adhesion, and the cadherins which are central to cell-cell adhesion. Our preliminary data suggest that the type-II p21-activated kinases (PAKs), a group of serine- threonine kinases, use a range of mechanisms to influence cell-matrix adhesion and cell-cell adhesion. The ability to regulate both adhesion systems places the PAKs as central players in coordination of cell adhesion dynamics. This proposal aims to understand the functional, cellular and molecular basis for this regulation. To address how they control cell-matrix and cell-cell adhesions we propose a combination of structural, biochemical and cellular approaches. In Aim 1 we test the hypothesis that Direct binding of PAK to cytoplasmic tails of integrin adhesion receptors regulates matrix adhesion and/or PAK signaling. We will conduct an extensive study employing structural, biophysical, biochemical and cell biological approaches. This will allow us to comprehensively understand how integrin adhesion receptors bind PAK serine-threonine kinases, and the functional consequences of such interactions on cell signaling, adhesion, motility and invasion. In Aim 2 we test the hypothesis that PAK targeted to cell-cell contacts phosphorylates b-catenin, triggering adhesion turnover and escape of individual cells from epithelial islands. We will determine the mechanisms by which PAKs drive colony escape, and the structural basis for PAK regulation of β-catenin. Finally, we will test whether the roles of PAKs in cell-cell and cell-ECM adhesion are linked. Our proposed work will define how PAKs regulate both integrin- mediated cell-matrix adhesion, and β-catenin-associated cell-cell adhesion, and therefore will provide new understanding of interconnections between cell-matrix and cell-cell adhesion via the type-II PAKs.