Connecting signaling with cytoskeleton: Abl and Arg in vertebrate gastrulation

描述(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，以控制脊椎动物早期发育中的细胞形态和运动。ABL和Arg是细胞质酪氨酸激酶家族的成员，该家族具有独特的肌动蛋白结合域。它们被认为在多种情况下调节细胞的形状和运动，如成纤维细胞的扩散和迁移以及神经炎在神经元中的延伸。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功能的分子机制是很重要的。在这个项目中，非洲爪蛙的原肠发育运动将作为模式系统来评估Abl和Arg在形态发生中的作用。本实验室的研究表明，Arg在非洲爪哇原肠发育过程中调节了两种类型的细胞运动，即头部中胚层迁移和主干中胚层会聚延伸。Arg调节细胞形态和膜突起，影响肌动蛋白组织。Arg能磷酸化两种效应蛋白CrkII和paxlin。将进行进一步的研究，以解决以下假设。1)受体酪氨酸激酶同时激活Abl和Arg来控制细胞运动。2)Abl和Arg与非正则WNT信号的串扰，以调制收敛扩展。3)CrkII作为Abl和Arg的效应器，部分介导了它们在原肠发育过程中的活性。4)Abl和Arg调节头部和躯干中胚层的肌动蛋白动态，从而影响细胞的形态和运动。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哇进行，但结果有望帮助阐明Abl和Arg如何在其他环境中调节细胞行为，例如在哺乳动物胚胎发生期间的形态发生和癌症转移中。

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.