Role of the actin cytoskeleton in insulin action.
Insulin has diverse effects on cells, including stimulation of glucose transport, gene expression, and alterations of cell morphology. The hormone mediates these effects by activation of signaling pathways which utilize, 1) adaptor 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 seemingly diverse pathways. Here, we discuss the involvement of the actin cytoskeleton in the propagation and regulation of insulin signals. In muscle cells in culture, insulin induces a rapid actin filament reorganization that coincides with plasma membrane ruffling and intense accumulation of pinocytotic vesicles. Initiation of these effects of insulin requires an intact actin cytoskeleton and activation of PI 3-kinase. We observed recruitment PI 3-kinase subunits and glucose transporter proteins to regions of reorganized actin. In both muscle and adipose cells, actin disassembly inhibited early insulin-induced events such as recruitment of glucose transporters to the cell surface and enhanced glucose transport. Additionally, actin disassembly inhibited more prolonged effects of insulin, including DNA synthesis and expression of immediate early genes such as c-fos. Intact actin filaments appear to be essential for mediation of early events such as association of Shc with Grb2 in response to insulin, which leads to stimulation of gene expression. Preliminary observations support a role for focal adhesion signaling complexes in insulin action. These observations suggest that the actin cytoskeleton facilitates propagation of the morphological, metabolic, and nuclear effects of insulin by regulating proper subcellular distribution of signaling molecules that participate in the insulin signaling pathway.
Tsakiridis
T
T
Division of Clinical Science, Department of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8.
Tong
P
P
Matthews
B
B
Tsiani
E
E
Bilan
P J
PJ
Klip
A
A
Downey
G P
GP
D000199:Actins / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004705:Endocytosis; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D008840:Microfilament Proteins / Q000502:physiology; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D051419:Paxillin; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D000199:Actins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D008840:Microfilament Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D051419:Paxillin; D010750:Phosphoproteins; D015638:Cytochalasin D; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005947:Glucose