Cell-cycle kinases to control endocytosis.

控制内吞作用的细胞周期激酶。

• 批准号: 155751-2012
• 负责人: Faure, RobertLouis
• 金额: $ 1.89万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=522668
• 关键词: Cell; cycle; kinases; control; endocytosis.

Insulin signaling is initiated by a receptor tyrosine kinase (RTK) located at the surface of target cells. Following insulin binding, there is rapid internalization of the activated complexes into the endosomal apparatus. Previously, endocytosis was thought to be a means to diminish the receptor signaling and hence allowing an appropriate response to sequential signaling events. However, active signaling may continue well after RTK internalization and the choice of endocytic routing can often determine the response. Despite the wide-ranging biological evidences of insulin signaling, the mechanism and role of endocytosis in determining its physiological outcome is still not understood. Proteome surveys of Golgi/endosomes fractions suggested recently that few and yet to be characterized mechanisms borrow elements from fondamental systems to regulate RTKs routing. Ongoing bioinformatics analyses using Mouse Genome Informatics (MGI) facilities show a network of functional links between proteins known to be involved in insulin receptor (IR) signaling and specific cellular functions and mechanisms. We have recently confirmed that a pool of Cdk2 is compartmentalized in endosomes where it associates with partners and controls insulin internalization (Fiset et al. 2011 Cellular Signaling 23: 911-919). We hypothesize that uncharacterized endosome-based protein complexes have acquired subfunctionality and coordinate IR routing with insulin action. We also hypothesize the presence of a new leader mechanism controlling insulin action: Cdk2 complexes reside on endosomes where they would be ideally positioned to participate in local regulatory circuits coordinating IR signaling and trafficking events.

胰岛素信号是由位于靶细胞表面的受体酪氨酸激酶（RTK）启动的。胰岛素结合后，活化复合物迅速内化进入内体。以前，内吞作用被认为是减少受体信号的一种手段，从而允许对序列信号事件作出适当的反应。然而，在RTK内化后，活跃的信号传导可能会持续很长时间，并且内吞途径的选择通常可以决定反应。尽管胰岛素信号的生物学证据广泛，但内吞作用在决定其生理结果中的机制和作用仍不清楚。高尔基体/核内体的蛋白质组学研究最近表明，很少有尚未表征的机制从基本系统中借用元件来调节rtk的路线。利用小鼠基因组信息学（MGI）设施进行的生物信息学分析显示，已知参与胰岛素受体（IR）信号传导和特定细胞功能和机制的蛋白质之间存在功能联系网络。我们最近证实，Cdk2库在核内体中被区分开，在那里它与伴侣相关并控制胰岛素内化（Fiset et al. 2011 Cellular Signaling 23: 911-919）。我们假设未表征的基于内体的蛋白复合物已获得亚功能，并与胰岛素作用协调IR路径。我们还假设存在一种控制胰岛素作用的新先导机制：Cdk2复合物驻留在核内体上，在那里它们将被理想地定位于参与协调IR信号传导和运输事件的局部调节回路。