Role of beta-arrestins in chemokine receptor signaling

β-抑制蛋白在趋化因子受体信号传导中的作用

• 批准号: 10391496
• 负责人: Adriano Marchese
• 金额: $ 32.05万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-11 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391496
• 关键词: Adaptor Signaling Protein; Anatomy; Attenuated; Binding; Biochemistry; Biophysics; CXCL12 gene; Cell Culture Techniques; Cell Survival; Cell physiology; Cell surface; Cells; Cellular biology; Cessation of life; Chemotaxis; Complex; Coupling; Data; Disease; Disseminated Malignant Neoplasm; Distant; Focal Adhesion Kinase 1; Focal Adhesions; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genetic; Health; Heterotrimeric GTP-Binding Proteins; Homing; In Vitro; Integrins; Knowledge; Lead; Ligands; Link; Liver; Lung; MAPK3 gene; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metastatic to; Modeling; Molecular; Molecular Biology; Molecular Conformation; Mutagenesis; Pathway interactions; Phosphorylation; Play; Process; Prognosis; Publishing; RNA Interference; Receptor Signaling; Reporting; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Site; Specific qualifier value; Spectrum Analysis; Stimulus; Surface; Techniques; Testing; Tissues; Vesicle; base; beta-arrestin; biophysical properties; cancer cell; cell motility; chemokine; chemokine receptor; design; innovation; insight; live cell imaging; lymph nodes; novel; overexpression; prevent; protein B; receptor; receptor binding; targeted treatment; therapeutic target; tumor progression

PROJECT SUMMARY The heterotrimeric G protein-coupled receptor (GPCR) C-X-C motif receptor 4 (CXCR4) and its cognate ligand CXCL12 play important roles in health and disease. A large body of evidence indicates that CXCR4 signaling is linked to cancer progression. CXCR4 expression and signaling in cancer correlates with poor prognosis2-5, mainly because cancer cells expressing CXCR4 colonize distant anatomical sites where CXCL12 is located, resulting in metastatic disease, the cause of most cancer related deaths. CXCR4 signaling regulates several aspects of cell physiology linked to cancer progression. This includes directed cell migration and cell survival, which occur via several discrete signaling pathways. Yet the mechanisms remain poorly understood. The focus of this proposal is on the signal transduction mechanisms that regulate CXCR4-mediated chemotaxis towards CXCL12. We recently reported that CXCR4-mediated chemotaxis occurs via a novel mechanism involving a complex formed between endocytic adaptor proteins b-arrestin1 (barr1) and STAM1 (barr1:STAM1). The barr1:STAM1 complex does not act on Akt or ERK-1/2 signaling pathways, but instead is necessary for activating focal adhesion kinase (FAK), which is also necessary for CXCL12 driven chemotaxis. FAK is typically linked to integrin signaling and focal adhesion dynamics, but these aspects of FAK function are not regulated by the barr1:STAM1 complex. Despite our contribution how barr1:STAM1 activates FAK downstream of CXCR4 to promote chemotaxis remains poorly understood. The overall objective of this proposal is to fill in knowledge gaps. Based on our published and preliminary studies we hypothesize that G protein-dependent barr1:STAM1 signaling spatially and temporally controls FAK activity required for CXCR4-dependent chemotaxis. To test this hypothesis we will pursue the following specific aims: Aim 1. To elucidate the role of CXCR4 site-specific phosphorylation on FAK activation; Aim 2. To identify the structural and biophysical properties of the barr1 interaction with STAM1; Aim 3. To elucidate the functional role of the barr1:STAM1 complex in chemotaxis. Because of the mechanistic focus of our proposal we will use cell culture models and other in vitro approaches spanning techniques in cell and molecular biology, genetics, biochemistry and biophysics plus advanced live cell imaging strategies and mass spectrometry approaches. At the conclusion of this project we will have learned novel signal transduction mechanisms by which barr1:STAM1 collaborate to activate FAK to promote chemotaxis. This is significant because it will reveal novel aspects of CXCR4 signaling that could be targeted therapeutically.

项目总结