Insulin receptor internalization: molecular mechanisms and physiopathological implications.

The initial interaction between insulin and its receptor on target cell surface is followed by a series of surface and intracellular steps which participate in the control of insulin action. Abnormalities of any of these steps could result in mishandling of the receptor leading to defective modulation of receptor number on the cell surface and to inappropriate cell sensitivity to the hormone. Thus, the identification of each of these steps as well as understanding the mechanisms governing them is obligatory to unravel some aspects of the pathogenesis of insulin resistance states. This was the goal of the studies we have carried out during recent years using combined molecular and cellular biology as well as biochemical techniques. These studies allowed us to propose the following ordered sequence of events: 1) insulin binds to receptors preferentially associated with microvilli on the cell surface; 2) insulin triggers receptor kinase activation and autophosphorylation which not only results in initiation of the various biological signals leading to insulin action but also in redistribution of the hormone-receptor complex in the plane of the membrane; 3) on the non-villous domain of the cell surface, insulin receptors anchor to clathrin-coated pits through specific "internalization sequences" present in their cytoplasmic juxtamembrane domain; 4) insulin-receptor complexes are internalized together with other receptors present in the same clathrin-coated pits through the formation of clathrin-coated vesicles; 5) the complexes are delivered to endosomes, the acidic pH of which induces the dissociation of insulin molecules from insulin receptors and their sorting in different directions; 6) insulin molecules are targetted to late endosomes and lysosomes where they are degraded; 7) receptors are recycled back to the cell surface in order to be reused.