Role of Receptor Internalization in Insulin Signalling

Many hormones and nutrient molecules are internalized into their target cells by the common mechanism of receptor-mediated endocytosis. This process involves the clustering of receptors into invaginated regions of the plasma membrane coated on their intracellular surface by the protein clathrin which forms a basket-like casing. This pitted region internalizes to form an independent vesicle which eventually loses its clathrin coat. Movement through the vesicular pathway allows intracellular sorting. The uptake of insulin appears to follow this path. In a variety of tissues, insulin stimulates the internalization of its own receptor upon binding (Hedo and Simpson, 1984; Krupp and Lane, 1982; Knutson et al., 1983). At some point along the endocytotic path, the hormone dissociates from the receptor and is degraded (Krupp and Lane, 1982). The receptor recycles to the plasma membrane where it can bind another insulin molecule to reinitiate the cycle. Besides stimulating receptor internalization, insulin stimulates rapid receptor autophosphorylation (Kohanski et al., 1986; White et al., 1985) activating the tyrosine kinase. The receptor is internalized in this state’(Backer et al., 1989). However, prior to recycling, the receptor is dephosphorylated (Backer et al., 1989) which inactivates the catalytic activity (Klein et al., 1987). How this kinase activity and endocytotic cycle is involved in insulin signalling is not well defined.