Cell-cycle kinases to control endocytosis.

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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.