Regulation of call adhesion in Xenopus

描述(申请人提供)：在非洲爪哇原肠发育过程中，胚层内和胚层之间粘附性的调节控制细胞-细胞和细胞-细胞外基质的相互作用，以调节形态发生。细胞黏附分子如钙粘附素、原钙黏附素和整合素参与了细胞黏附和细胞运动的差异性调节。已知的参与中胚层形态形成的生长因子，如Wnt和激活素/节点，也影响中胚层的形态发生和细胞形状。本项目的重点是揭示Flrt3(富含亮氨酸重复序列的跨膜蛋白3)在非洲爪哇早期形态发生中的分子功能。在揭示Flrts功能的过程中，我们做了以下有趣的观察：第一，在原肠胚期胚胎的退化边缘细胞中，Flrt3和RND1共表达。其次，Flrt3的过表达阻止了钙粘附素介导的细胞黏附，而这种作用需要RND1的存在。第三，Flrt3与RNDL在物理上相互作用。我们现在建议解决以下问题来阐明由转化生长因子-B信号介导的形态发生事件背后的分子机制：目的1：Flrt3和RND1是如何调节原肠形成运动的？目标2：Flrt3如何与RND1相互作用？目的3.Flrt3和RND1是如何调节钙粘附素介导的黏附的？目的4：还有哪些分子介导Flrt3和RNDL信号？这项提议概述了一项尝试，从细胞外水平到影响细胞黏附的细胞内信号事件，描绘了Flrt3跨膜蛋白的功能。许多研究已将小GTP酶和黏附分子(如钙粘附素)的异常表达与肿瘤的发生和转移联系起来。由于肿瘤的发展往往与胚胎发育的过程平行，细胞的快速增殖和广泛的细胞运动，我们的工作可能为更好地理解肿瘤的发生提供直接的相关性。

DESCRIPTION (provided by applicant): During Xenopus gastrulation, the modulation of adhesive properties within and between the germ layers controls cell-cell and cell-extracellular matrix interactions to regulate morphogenesis. Cell adhesion molecules such as cadherins, protocadherins and integrins have been implicated in the differential regulation of cell adhesion and cell movement. Growth factors known to be involved in mesoderm patterning such as Wnt and activin/nodal also influence mesodermal morphogenesis and cell shape. The focus of this project is to uncover the molecular function of FLRT3 (Fibronectin Leucine-rich Repeat Transmembrane protein 3) in early Xenopus morphogenesis. In the process of uncovering FLRTS's function, we have made the following intriguing observations: First, FLRT3 and Rnd1 are coexpressed in the involuting marginal cells of gastrula stage embryos. Second, overexpression of FLRT3 blocks cadherin-mediated adhesion in the treated cells and this effect requires the presence of Rnd1. Third, FLRT3 interacts physically with Rndl. We now propose to address the following questions to elucidate the molecular mechanisms behind the morphogenetic events mediated by TGF-B signaling: Aim 1: How do FLRT3 and Rnd1 function to regulate gastrulation movements? Aim 2: How does FLRT3 interact with Rnd1? Aim 3. How is cadherin-mediated adhesion modulated by FLRT3 and Rnd1? Aim 4: What other molecules mediate FLRT3 and Rndl signaling? This proposal outlines an attempt to delineate the function of the FLRT3 transmembrane protein from the extracellular level down through the intracellular signaling events that affect cell adhesion. Numerous studies have linked aberrant expression of small GTPases and adhesion molecules such as cadherins to oncogenesis and metastasis. As the development of tumors often parallels the process of embryonic development in terms of rapid cell proliferation and extensive cellular movements, our work may provide direct relevance for a better understanding of tumorigenesis.