Insulin internalization and other signaling pathways in the pleiotropic effects of insulin

Insulin is the major anabolic hormone in humans and affects multiple cellular processes. Insulin rapidly regulates short-term effects on carbohydrate, lipid, and protein metabolism and is also a potent growth factor controlling cell proliferation and differentiation. The metabolic and growth-related effects require insulin binding to its receptor and receptor phosphorylation. Evidence suggests these events result in subsequent substrate phosphorylation and activation of multiple signaling pathways involving Src homology domain-containing proteins and the internalization of the insulin:receptor complex. The role of insulin internalization in insulin action is largely speculative. For more than two decades, extensive investigation has been carried out by numerous laboratories of the mechanisms by which insulin causes its pleiotropic responses and the cellular processing of insulin receptors. This chapter reviews our current knowledge of the phosphorylation signaling pathways activated by insulin and presents evidence that substrates other than insulin receptor substrate-1 are involved in insulin's regulation of immediate-early gene expression. We also review the mechanisms involved in insulin internalization and present evidence that internalization may play a key role in insulin action through both signal transduction processes and translocation of insulin to the cell cytoplasm and nucleus.