Regulation of Leukocyte Migration by WD40 Repeat Proteins

WD40 重复蛋白对白细胞迁移的调节

• 批准号: 8728939
• 负责人: Songhai Chen
• 金额: $ 28.69万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728939
• 关键词: Abnormal Cell; Autoimmune Diseases; Binding; Biological; Cardiovascular Diseases; Cell Surface Receptors; Cells; Characteristics; Chemotactic Factors; Chemotaxis; Development; Disease; Embryonic Development; Equilibrium; Family; Feedback; Figs - dietary; G-Protein-Coupled Receptors; GTP-Binding Proteins; Generations; Health; Heterotrimeric GTP-Binding Proteins; Human; Immigration; Immune response; Immunologic Surveillance; Knowledge; Leukocytes; Life; Mediating; Membrane; Modeling; Molecular; Neoplasm Metastasis; Process; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Work; Wound Healing; angiogenesis; base; cardiovascular neoplasm; cell motility; dimer; directional cell; extracellular; innovation; migration; neutrophil; novel; protein activation; receptor; receptors for activated C kinase; research study; response; tumor

DESCRIPTION (provided by applicant): Cell migration is a fundamental process required for embryogenesis, angiogenesis, wound healing and immune responses, and abnormalities in this process are associated with a plethora of pathological conditions including autoimmune diseases, arthrosclerosis and tumor metastasis. Cell migration is regulated by chemoattractants acting on cell-surface receptors belonging to the large family of G protein-coupled receptors. These receptors typically couple to G proteins of the Gi/o class, and mediate their functions through Gbg dimers. Although the essential role of Gbg in cell migration has been well established, it is still unclear how Gbg activate downstream effectors to generate a highly polarized intracellular signal that acts as an internal "compass" to drive directional cell migration. We have recently identified novel interactions between Gbg and the WD40 repeat proteins RACK1 (receptor for activated C kinase 1) and WDR26. Based on the findings that RACK1 and WDR26 are localized at the leading edge of a polarized leukocyte and negatively and positively regulate Gbg signaling, respectively, we hypothesize that reciprocal interactions of Gbg with WDR26 and RACK1 are important positive and negative feedback regulations for the coordinated Gbg signaling at the leading edge that drives leukocyte polarization and directed migration. In Aim 1, we will explore the molecular mechanism by which WDR26 interacts with Gbg and its effectors including PI3Ks and PLCb to promote Gbg signaling and generate a highly polarized intracellular response at the leading edge for leukocyte migration. In Aim 2, we will determine how RACK1 restricts Gbg signaling for the generation of a locally amplified signal at the leading edge and for signal adaptation and directional sensing. Finally, we will dissect the molecular signals that control the reciprocal interactions of WDR26 and RACK1 with Gbg and determine the impact of the balance of these interactions on leukocyte migration. These studies have the potential to close a critical gap in our understanding of how chemoattractants transmit through Gbg to generate a spatially localized cellular signal at the leading edge that drives leukocyte migration, and to unveil a novel mechanism of regulating chemotaxis at the level of G proteins upstream to all known signaling pathways essential for cell migration. Given the involvement of abnormal leukocyte migration in many pathological conditions, the proposed research will be vital for identifying novel targets to enable selective interference of the signaling pathways related to disease development. Thus, this work has high biological significance and potential impact on human health.

描述（由申请人提供）：细胞迁移是胚胎发生、血管生成、伤口愈合和免疫应答所需的基本过程，并且该过程中的异常与包括自身免疫性疾病、关节硬化和肿瘤转移在内的多种病理状况相关。细胞迁移是由化学引诱剂作用于属于G蛋白偶联受体大家族的细胞表面受体来调节的。这些受体通常与Gi/o类G蛋白偶联，并通过Gbg二聚体介导其功能。虽然Gbg在细胞迁移中的重要作用已经得到很好的确立，但仍不清楚Gbg如何激活下游效应物以产生高度极化的细胞内信号，该信号充当内部“指南针”以驱动定向细胞迁移。我们最近发现了新的Gbg和WD 40重复蛋白RACK 1（活化C激酶1受体）和WDR 26之间的相互作用。基于RACK 1和WDR 26定位于极化白细胞的前沿并分别负性和正性调节Gbg信号传导的发现，我们假设Gbg与WDR 26和RACK 1的相互作用对于驱动白细胞极化和定向迁移的前沿的协调Gbg信号传导是重要的正性和负性反馈调节。在目标1中，我们将探索WDR 26与Gbg及其效应物（包括PI 3 Ks和PLCb）相互作用以促进Gbg信号传导并在白细胞迁移的前沿产生高度极化的细胞内反应的分子机制。在目标2中，我们将确定RACK 1如何限制Gbg信令以在前沿生成局部放大信号以及用于信号自适应和定向感测。最后，我们将剖析控制WDR 26和RACK 1与Gbg相互作用的分子信号，并确定这些相互作用的平衡对白细胞迁移的影响。这些研究有可能关闭一个关键的差距，在我们的理解如何通过Gbg的化学引诱物传输产生一个空间定位的细胞信号的前沿，驱动白细胞迁移，并揭示了一种新的机制，调节趋化性的水平上的G蛋白上游的所有已知的信号通路细胞迁移必不可少的。鉴于异常白细胞迁移参与许多病理条件，拟议的研究将是至关重要的，以确定新的目标，使选择性干扰的信号通路相关的疾病发展。因此，这项工作具有很高的生物学意义和对人类健康的潜在影响。