Cell-cycle kinases to control endocytosis.

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，激活的复合体迅速内化到内体器官中。以前，内吞作用被认为是一种减少受体信号传递的手段，从而允许对连续的信号事件做出适当的反应。然而，在RTK内化后，活跃的信号可能会很好地继续，内吞路线的选择通常可以决定反应。尽管有广泛的胰岛素信号生物学证据，但内吞作用决定其生理结果的机制和作用仍不清楚。最近对高尔基体/内吞体组分的蛋白质组学研究表明，很少有机制借用基础系统中的元件来调节RTK的路径。利用小鼠基因组信息学(MGI)设施进行的生物信息学分析表明，参与胰岛素受体(IR)信号传递的蛋白质与特定的细胞功能和机制之间存在着一个功能联系的网络。我们最近证实，CDK2池在内体中被分隔，在那里它与伴侣联系并控制胰岛素内化(Fiset等人。2011蜂窝信令23：911-919)。我们假设，未特化的基于内吞体基的蛋白质复合体已经获得了亚功能，并协调了IR的传递和胰岛素的作用。我们还假设存在一个控制胰岛素作用的新的先导机制：CDK2复合体驻留在内小体上，在那里它们将处于理想的位置，参与协调IR信号和贩运事件的局部调节电路。

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.