"A signaling integrator plays a critical role in regulating cell migration"

描述（由申请人提供）：调节细胞迁移的信号机制在许多生物学和病理过程中都很重要，包括胚胎发生、炎症反应、组织修复和再生、癌症、关节炎、动脉粥样硬化、骨质疏松症和先天性发育性脑缺陷，但人们对其信号机制还不太了解。一个新兴的概念是，整合信号成分来协调调节迁移过程的分子，如肌动蛋白重组、粘附组装和拆卸（翻转）以及极性的建立，对这一过程至关重要。我们假设，多结构域蛋白Asef2通过整合这些过程的关键信号成分来调节细胞迁移，从而发挥这种功能。我们的初步工作已经产生了一些可行的假设，这项建议的目的是严格检验这些具体目标中概述的假设。我将验证Asef2通过其整合分子信号的能力是迁移的关键调节剂的假设，这对迁移过程很重要。我们将确定介导Asef2功能的结构域，以深入了解其调节细胞迁移的分子机制。在Specific Aim II中，我们将验证Asef2将激酶（如Akt和Rho家族GTPase信号传导）聚集在一起以调节细胞迁移的假设。为此，我们将使用表达构建、基于突变的策略、药理学抑制剂和siRNA研究来验证这一假设。我们的工作模型是，Asef2信号协调调节激酶和Rho gtpase的活性，刺激边缘粘附的快速周转，从而增强细胞迁移。特异性Aim III将确定Asef2信号成分，如Akt和其他激酶效应器，是否调节前缘粘附的周转。在这个目标中，我们将通过使用我们开发的研究粘附转换的新定量分析来检验我们的假设。本提案中概述的研究将有助于更好地理解Asef2调节细胞迁移的信号机制。

DESCRIPTION (provided by applicant): The signaling mechanisms that regulate cell migration are not well understood despite its importance in numerous biological and pathological processes, including embryogenesis, the inflammatory response, tissue repair and regeneration, cancer, arthritis, atherosclerosis, osteoporosis, and congenital developmental brain defects. An emerging concept is that molecules, which integrate signaling components to coordinately regulate processes underlying migration, such as actin reorganization, adhesion assembly and disassembly (turnover), and the establishment of polarity, are critical for this process. We hypothesize that the multi-domain containing protein, Asef2, functions in this capacity by integrating critical signaling components of these processes to regulate cell migration. Our preliminary work has lead to working hypotheses and the objective of this proposal is to rigorously test these hypotheses as outlined in the specific aims. Specific Aim I will test the hypothesis that Asef2 is a critical regulator of migration through its ability to integrate molecular signals, which are important to this process. We will determine the domains that mediate this function of Asef2 to gain insight into the molecular mechanisms by which it regulates cell migration. In Specific Aim II, we will test the hypothesis that Asef2 brings together kinases, such as Akt, and Rho family GTPase signaling to modulate cell migration. In this aim, we will use expression constructs, mutant based strategies, pharmacological inhibitors, and siRNA studies to test this hypothesis. Our working model is that Asef2 signaling coordinately regulates the activities of kinases and Rho GTPases to stimulate the rapid turnover of leading edge adhesions, which leads to enhanced cell migration. Specific Aim III will determine if Asef2 signaling components, such as Akt and other kinase effectors, regulate the turnover of leading edge adhesions. In this aim, we will test our hypothesis by using new quantitative assays that we developed to study adhesion turnover. The studies outlined in this proposal will lead to a greater understanding of the signaling mechanisms by which Asef2 regulates cell migration. PUBLIC HEALTH RELEVANCE: Cell migration is central to many biological and pathological processes, such as cancer, arthritis, atherosclerosis, and congenital brain defects. Understanding the molecules that regulate migration will lead to new therapeutic approaches to treating these disorders. The goal of this proposal is to identify molecules that are critical regulators of cell migration.