Phosphorylation of Gap Junction Proteins

在脊椎动物中，缝隙连接由连接蛋白家族的蛋白质组成，该家族包含 人类中大约有20个成员。离子、氨基酸、核苷酸、其他代谢物和一些 二级信使(如钙、cAMP、cGMP、IP3)很容易通过缝隙连接，而 大分子被排除在外。GJC在许多细胞过程中至关重要，包括对细胞的控制 增殖、胚胎发育、细胞分化与多种动态平衡的协调 静止细胞中的细胞功能。缝隙连接蛋白43(Cx43)是通过 磷酸化及其与其他蛋白质的相互作用。这项建议集中在这两个人的作用 监管过程在静止期间发挥作用，以及它们如何随着核扩散而变化。连接蛋白 磷酸化可以调节缝隙连接通讯(GJC)的水平。Cx43的磷酸化位于 多个丝氨酸残基存在于蛋白质的胞质C-末端区域。广泛的证据 表明GJC在细胞周期中发生变化，我们有证据表明细胞改变了它们的Cx43 当它们从静止状态过渡到细胞周期时，它们会发生磷酸化。我们假设Cx43 磷酸化改变了与Cx43相互作用的蛋白质，并可以改变Cx43运输的动力学， 以细胞周期阶段特有的方式影响重要生物学的组装、门控和周转 细胞迁移和增殖等过程。这项研究的重要性从以下方面得到了例证 连接蛋白定位和GJC的变化与细胞增殖和 在伤口愈合过程中发生迁移，在癌变过程中失去生长控制。我们假设 Cx43的磷酸化变化与这些过程有关，从而影响细胞功能。

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.