Molecular mechanisms of differential intracellular signaling from the insulin receptor.

Binding of insulin to the insulin receptor (IR) leads to a cascade of intracellular signaling events, which regulate multiple biological processes such as glucose and lipid metabolism, gene expression, protein synthesis, and cell growth, division, and survival. However, the exact mechanism of how the insulin-IR interaction produces its own specific pattern of regulated cellular functions is not yet fully understood. Insulin analogs, anti-IR antibodies as well as synthetic insulin mimetic peptides that target the two insulin-binding regions of the IR, have been used to study the relationship between different aspects of receptor binding and function as well as providing new insights into the structure and function of the IR. This review focuses on the current knowledge of activation of the IR and how activation of the IR by different ligands initiates different cellular responses. Investigation of differential activation of the IR may provide clues to the molecular mechanisms of how the insulin-receptor interaction controls the specificity of the downstream signaling response. Differences in the kinetics of ligand-interaction with the IR, the magnitude of the signal as well as its subcelllar location all play important roles in determining/eliciting the different biological responses. Additional studies are nevertheless required to dissect the precise molecular mechanisms leading to the differential signaling from the IR.