Connecting signaling with cytoskeleton: Abl and Arg in vertebrate gastrulation

描述（由申请人提供）：拟议研究的总体目标是了解细胞质酪氨酸激酶Abl和Arg如何调节生长因子信号下游的肌动蛋白重塑，以控制早期脊椎动物发育期间的细胞形态和运动。Abl和Arg是唯一具有肌动蛋白结合结构域的胞质酪氨酸激酶家族的成员。它们在几种情况下参与调节细胞形状和运动性，例如成纤维细胞的扩散和迁移以及神经元中神经炎的扩展。Abl和Arg参与影响人类健康和疾病的过程，包括例如微生物入侵和癌症进展。因此，深入了解Abl和Arg功能的分子机制非常重要。在这个项目中，原肠胚运动在非洲爪蟾非洲爪蟾将被用作模型系统，以评估的作用Abl和精氨酸的形态发生。在本实验室进行的研究表明，精氨酸调制两种类型的细胞运动在非洲爪蟾原肠胚，头部中胚层迁移和躯干中胚层会聚延伸。精氨酸调节细胞的形状和膜突起，影响肌动蛋白的组织。Arg可以磷酸化两种效应蛋白CrkII和桩蛋白。将进行进一步的研究，以解决以下假设。1)受体酪氨酸激酶激活Abl和Arg以控制细胞运动。2)Abl和Arg与非规范Wnt信号的串扰以调制会聚扩展。3)CrkII作为Abl和Arg的效应物，部分介导它们在原肠胚形成中的活动。4)Abl和Arg调节头部和躯干中胚层中的肌动蛋白动力学以影响细胞形态和运动。从这些研究中收集的数据将为Abl和Arg对细胞运动的机械控制提供重要的见解。虽然研究将在非洲爪蟾中进行，但结果有望有助于阐明Abl和Arg如何在其他情况下调节细胞行为，例如哺乳动物胚胎发生期间的形态发生和癌症转移。

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to understand how the cytoplasmic tyrosine kinases Abl and Arg regulate actin remodeling downstream of growth factor signals to control cell morphology and movements during early vertebrate development. Abl and Arg are members of a family of cytoplasmic tyrosine kinases that uniquely have actin-binding domains. They have been implicated in regulating cell shape and motility in several contexts, such as spreading and migration of fibroblasts and extension of neuritis in neurons. Abl and Arg are involved in processes that impact on human health and diseases, including for example microbial invasion and cancer progression. In depth understanding of the molecular mechanisms underlying the functions of Abl and Arg is thus important. In this project, gastrulation movements in African clawed frog Xenopus laevis will be used as the model system to assess the roles of Abl and Arg in morphogenesis. Studies carried out in this laboratory revealed that Arg modulated two types of cell motility during Xenopus gastrulation, that of head mesoderm migration and trunk mesoderm convergent extension. Arg regulated cell shapes and membrane protrusions and affected actin organization. Arg could phosphorylate two effector proteins CrkII and paxillin. Further research will be conducted to address the following hypotheses. 1) Receptor tyrosine kinases activate both Abl and Arg to control cell movements. 2) Abl and Arg crosstalk with non-canonical Wnt signals to modulate convergent extension. 3) CrkII acts as an effector of Abl and Arg to partially mediate their activities in gastrulation. 4) Abl and Arg modulate actin dynamics in both the head and the trunk mesoderm to influence cell morphology and motility. Data collected from these studies will provide crucial insight into mechanistic control of cell movements by Abl and Arg. Though research will be performed in Xenopus, results promise to help shed light on how Abl and Arg modulate cell behaviors in other contexts, such as in morphogenesis during mammalian embryogenesis and in cancer metastasis.