Role of the actin cytoskeleton in insulin action

Insulin has diverse effects on cells, including stimulation of glucose tran sport, gene expression, and alterations of cell morphology. The hormone med iates these effects by activation of signaling pathways which utilize, 1) a daptor molecules such as the insulin receptor substrates (IRS), the Src and collagen homologs (Shc), and the growth factor receptor binding protein 2 (Grb2); 2) lipid kinases such as phosphatidylinositol 3-kinase (PI 3-Kinase ); 3) small G proteins; and 4) serine, threonine, and tyrosine kinases. The activation of such signaling molecules by insulin is now well established, but we do not yet fully understand the mechanisms integrating these seemin gly diverse pathways. Here, we discuss the involvement of the actin cytoske leton in the propagation and regulation of insulin signals. In muscle cells in culture, insulin induces a rapid actin filament reorganization that coi ncides with plasma membrane ruffling and intense accumulation of pinocytoti c vesicles. Initiation of these effects of insulin requires an intact actin cytoskeleton and activation of PI 3-kinase. We observed recruitment PI 3-k inase subunits and glucose transporter proteins to regions of reorganized a ctin. In both muscle and adipose cells, actin disassembly inhibited early i nsulin-induced events such as recruitment of glucose transporters to the ce ll surface and enhanced glucose transport. Additionally, actin disassembly inhibited more prolonged effects of insulin, including DNA synthesis and ex pression of immediate early genes such as c-fos. Intact actin filaments app ear to be essential for mediation of early events such as association of Sh c with Grb2 in response to insulin, which leads to stimulation of gene expr ession. Preliminary observations support a role for focal adhesion signalin g complexes in insulin action. These observations suggest that the actin cy toskeleton facilitates propagation of the morphological, metabolic, and nuc lear effects of insulin by regulating proper subcellular distribution of si gnaling molecules that participate in the insulin signaling pathway. (C) 19 99 Wiley-Liss, Inc.