Phosphorylation of Gap Junction Proteins

间隙连接蛋白的磷酸化

• 批准号: 7940515
• 负责人: PAUL D. LAMPE
• 金额: $ 25.37万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7940515
• 关键词: Affect; Amino Acid Substitution; Amino Acids; Binding; Biological Process; C-terminal; Calcium; Cell Cycle; Cell Cycle Stage; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Collection; Communication; Connexin 43; Connexins; Cyclic AMP; Cyclic GMP; Diffusion; Embryonic Development; Event; Family; Gap Junctions; Growth; Human; Ions; Kinetics; Knock-in Mouse; Left; Link; Maps; Membrane; Mitogen-Activated Protein Kinases; Mitosis; Mutation; Nucleotides; Phospho-Specific Antibodies; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Process; Property; Protein Kinase C; Protein Region; Proteins; Recycling; Regulation; Research; Research Personnel; Role; Scaffolding Protein; Second Messenger Systems; Serine; Signal Transduction; Site; Skin; Techniques; Testing; Transgenic Mice; Transgenic Organisms; Vertebrates; Wound Healing; carcinogenesis; cell motility; improved; in vivo; keratinocyte; link protein; macromolecule; member; migration; mutant; novel; programs; second messenger; small molecule; trafficking; wound

In vertebrates, gap junctions are composed of proteins from the connexin family which contains approximately 20 members in humans. Ions, amino acids, nucleotides, other metabolites and some secondary messengers (e.g., calcium, cAMP, cGMP, IP3) readily pass through gap junctions while macromolecules are excluded. GJC is critically important in many cell processes including control of cell proliferation, embryonic development, cell differentiation and the coordination of a variety of homeostatic cellular functions in quiescent cells. The gap junction protein connexin43 (Cx43) is regulated via phosphorylation and its interactions with other proteins. This proposal focuses on the role that these two regulatory processes play during quiescence and how they change with proliferation. Connexin phosphorylation can modulate the levels of gap junctional communication (GJC). Cx43 is phosphorylated at multiple serine residues found in the cytoplasmic, C-terrninal region of the protein. Extensive evidence indicates that GJC changes during the cell cycle, and we have evidence that cells change their Cx43 phosphorylation as they transition from quiescence through the cell cycle. We hypothesize that Cx43 phosphorylation alters the proteins that interact with Cx43 and can change the kinetics of Cx43 trafficking, assembly, gating, and turnover in a cell cycle stage-specific manner that affects important biological processes such as cell migration and proliferation. The importance of this research is exemplified by the linkage of changes in connexin localization and GJC to the exquisite control of cellular proliferation and migration during wound healing and with a loss of growth control during carcinogenesis. We hypothesize that Cx43 phosphorylation changes are linked to these processes in a way that affects cellular function.

在脊椎动物中，间隙连接由来自连接蛋白家族的蛋白质组成，其包含 大约有20个成员。离子、氨基酸、核苷酸、其他代谢物和一些 第二信使（例如，钙、cAMP、cGMP、IP3）容易通过间隙连接， 排除了大分子。GJC在许多细胞过程中是至关重要的，包括控制细胞的生长， 增殖、胚胎发育、细胞分化和各种稳态的协调 在静止细胞中的细胞功能。差距连接蛋白连接蛋白43（Cx43）通过以下途径调节： 磷酸化及其与其他蛋白质的相互作用。这一建议侧重于这两个方面的作用， 调节过程在静止期发挥作用，以及它们如何随着增殖而变化。连接蛋白 磷酸化可以调节间隙连接通讯（GJC）的水平。Cx43磷酸化， 在蛋白质的胞质C端区域发现的多个丝氨酸残基。大量证据 表明GJC在细胞周期中发生变化，我们有证据表明细胞改变其Cx43 磷酸化，因为它们通过细胞周期从静止过渡。我们假设Cx43 磷酸化改变了与Cx43相互作用的蛋白质并可改变Cx43运输的动力学， 以细胞周期阶段特异性的方式组装、门控和周转，影响重要的生物学特性。 例如细胞迁移和增殖。这项研究的重要性体现在 连接蛋白定位和GJC的变化与细胞增殖的精确控制之间的联系， 在伤口愈合过程中的迁移，并在癌变过程中失去生长控制。我们假设 Cx43磷酸化的变化与这些过程有关，影响细胞功能。