Connecting signaling with cytoskeleton: Abl and Arg in vertebrate gastrulation

连接信号传导与细胞骨架：脊椎动物原肠胚形成中的 Abl 和 Arg

• 批准号: 8368467
• 负责人: CHENBEI CHANG
• 金额: $ 32.23万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8368467
• 关键词: Actins; Address; Adult; Affect; African; Binding; Biochemical; Biological Models; Breast Cancer Cell; Cell Polarity; Cell Shape; Cell Surface Extensions; Cells; Cellular Morphology; Characteristics; Cytoskeleton; DNA Sequence Rearrangement; Data; Development; Developmental Process; Disease; Disseminated Malignant Neoplasm; Embryonic Development; Employment; Family; Fiber; Fibroblast Growth Factor Receptors; Fibroblasts; Goals; Grant; Growth Factor; Head; Health; Homeostasis; Human; Laboratories; Life; Light; Mammalian Cell; Mediating; Membrane; Mesoderm; Modeling; Modification; Molecular; Morphogenesis; Movement; Neoplasm Metastasis; Neuritis; Neurons; PDGFRB gene; Phosphorylation; Phosphotransferases; Process; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Research; Role; Signal Transduction; Testing; Time; Tissues; Translating; Video Microscopy; Xenopus; Xenopus laevis; Xenopus sp.; cell behavior; cell motility; gastrulation; insight; member; microbial; migration; neuron development; new therapeutic target; paxillin; receptor-mediated signaling; tumor progression

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. PUBLIC HEALTH RELEVANCE: Research proposed in this grant addresses the molecular mechanisms via which the cytoplasmic tyrosine kinases Abl and Arg control cell movements. Abl and Arg have been implicated in many processes that affect human health and diseases, including neuronal development, microbial invasion, and cancer progression. Data gathered from our studies will enhance our understanding on basic mechanisms underlying Abl and Arg function, help to add crucial insight in cancer metastasis and invasion, and contribute to the search for new therapeutic targets for metastatic cancers associated with impaired Abl and Arg signals.

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过程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，独特地具有肌动蛋白结合域。它们在多种情况下参与调节细胞形状和运动，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，包括微生物入侵和癌症进展。因此，深入了解 Abl 和 Arg 功能背后的分子机制非常重要。在该项目中，非洲爪蛙 Xenopus laevis 的原肠胚形成运动将用作模型系统来评估 Abl 和 Arg 在形态发生中的作用。该实验室进行的研究表明，Arg 在非洲爪蟾原肠胚形成过程中调节两种类型的细胞运动，即头部中胚层迁移和躯干中胚层会聚延伸。 Arg 调节细胞形状和膜突出并影响肌动蛋白组织。 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来解决以下假设。 1) 受体酪氨酸激酶激活 Abl 和 Arg 来控制细胞运动。 2) Abl 和 Arg 与非规范 Wnt 信号串扰以调制收敛扩展。 3) CrkII 作为 Abl 和 Arg 的效应器，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。尽管研究将在非洲爪蟾中进行，但结果有望帮助阐明 Abl 和 Arg 在其他情况下如何调节细胞行为，例如在哺乳动物胚胎发生期间的形态发生和癌症转移中。 公共健康相关性：本次资助提出的研究涉及细胞质酪氨酸激酶 Abl 和 Arg 控制细胞运动的分子机制。 Abl 和 Arg 与影响人类健康和疾病的许多过程有关，包括神经元发育、微生物入侵和癌症进展。我们的研究收集的数据将增强我们对 Abl 和 Arg 功能基本机制的理解，有助于增加对癌症转移和侵袭的重要见解，并有助于寻找与 Abl 和 Arg 信号受损相关的转移性癌症的新治疗靶点。