During the past several years, we have made enormous progress in our understanding of the cellular mechanisms involved in insulin receptor signaling. These findings have come about due to the coordinate use of physical, molecular, and cellular biological approaches to the complex issues of intracellular protein-protein interactions, subcellular localization and activation of enzyme activities. Although we have come a long way, we still have a lot to learn before the entire scheme of insulin signaling is established at the molecular level. Presently, there are several pressing issues that need to be resolved in order to determine the basis for the mitogenic and metabolic actions of insulin. For example, one important issue is the molecular basis of receptor signaling specificity. Does this result from the regulation of the signal amplitude (receptor number and/or hormone dose) or from the intrinsic cellular context of a particular receptor. If cell context-dependent, is this due to receptor substrate specificity, site specific phosphorylation, and/or combinational associations within a defined group of effectors. Although some progress is being made examining the potential importance of effector compartmentalization, are the temporal patterns of activation events important? Finally, what are the unidentified factors which may be necessary in the pleiotropic actions of insulin? These issues will only be resolved once each of the biochemical pathways leading to a particular biological response have been defined. We are looking forward to a very exciting future for the elucidation of the molecular basis of insulin action.
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