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: 8691898
• 负责人: CHENBEI CHANG
• 金额: $ 31.31万
• 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/8691898
• 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.

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细胞形态和运动。 ABL和ARG是唯一具有肌动蛋白结合域的细胞质酪氨酸激酶家族的成员。它们与在多种情况下调节细胞形状和运动性有关，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参与了影响人类健康和疾病的过程，包括微生物侵袭和癌症进展。因此，深入了解ABL和ARG功能的分子机制很重要。在这个项目中，非洲爪蛙爪蟾乳突中的胃运动将被用作评估ABL和ARG在形态发生中的作用的模型系统。在该实验室进行的研究表明，ARG在异武胃中调节了两种类型的细胞运动性，即中胚层迁移和躯干中胚层收敛延伸。 ARG调节细胞形状和膜突起，并影响肌动蛋白组织。 ARG可以磷酸化两种效应蛋白CRKII和PAXILLIN。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串扰具有非典型的Wnt信号，以调节收敛扩展。 3）CRKII充当ABL的效应子，并在部分介导了其在胃肠道中的活动。 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至关重要的见解。尽管将在爪蟾进行研究，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和癌症转移中的形态发生。