Insulin Receptor Signals Regulating GLUT4 Translocation and Actin Dynamics

Abstract

Abstract. In skeletal muscle and adipose tissue, insulin-stimulated glucose uptake is dependent upon translocation of the insulin-responsive glucose transporter GLUT4 from intracellular storage compartments to the plasma membrane. This insulin-induced redistribution of GLUT4 protein is achieved through a series of highly organized membrane trafficking events, orchestrated by insulin receptor signals. Recently, several key molecules linking insulin receptor signals and membrane trafficking have been identified, and emerging evidence supports the importance of subcellular compartmentalization of signaling components at the right time and in the right place. In addition, the translocation of GLUT4 in adipocytes requires insulin stimulation of dynamic actin remodeling at the inner surface of the plasma membrane (cortical actin) and in the perinuclear region. This results from at least two independent insulin receptor signals, one leading to the activation of phosphatidylinositol (PI) 3-kinase and the other to the activation of the Rho family small GTP-binding protein TC10. Thus, both spatial and temporal regulations of actin dynamics, both beneath the plasma membrane and around endomembranes, by insulin receptor signals are also involved in the process of GLUT4 translocation.

The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes

“…These changes may largely be due to phosphorylations [31,46] and/or other PTMs. Insulin elicits rapid dynamic remodelling of actin filaments, and this is necessary for GLUT4 translocation [47,48]. MYH2 phosphorylation has been implicated to participate in GLUT4 storage vesicle translocation [49].…”

Over-expression of NYGGF4 inhibits glucose transport in 3T3-L1 adipocytes via attenuated phosphorylation of IRS-1 and Akt

“…Effects of NYGGF4 on basal and insulin-stimulated GLUT4 translocation In adipocytes, insulin-stimulated glucose uptake is dependent on translocation of the insulinresponsive glucose transporter GLUT4 from intracellular storage compartments to the PM [10,11] . Therefore, using dif-ferentiated 3T3-L1 adipocytes, we examined the effects of NYGGF4 on GLUT4 translocation to the PM in response to insulin.…”

Type 1 Diabetes Mellitus: Redefining the Future of Cardiovascular Complications with Novel Treatments

“…Insulin receptor is a member of the receptor tyrosine kinase family (De Meyts and Whittaker, 2002;Kanzaki, 2006;Klarlund et al, 2003;Lawrence et al, 2007;Stern, 1995;Ward et al, 2008). It is a large cell-surface multi-domain glycoprotein that consists of two extracellular -subunits (MW~125 kDa) and two transmembrane -subunits (MW~95 kDa) (Kanzaki, 2006;Klarlund et al, 2003;Lawrence et al, 2007;Stern, 1995;Ward et al, 2008) linked by disulfide bonds (Kanzaki, 2006;Lawrence et al, 2007) into an 2 2 heterotetrameric complex (Kanzaki, 2006).…”

“…It is a large cell-surface multi-domain glycoprotein that consists of two extracellular -subunits (MW~125 kDa) and two transmembrane -subunits (MW~95 kDa) (Kanzaki, 2006;Klarlund et al, 2003;Lawrence et al, 2007;Stern, 1995;Ward et al, 2008) linked by disulfide bonds (Kanzaki, 2006;Lawrence et al, 2007) into an 2 2 heterotetrameric complex (Kanzaki, 2006). Extracellular -subunits contain the insulin-binding site (Klarlund et al, 2003) while intracellularly transmembrane -subunits contain the insulin-regulated tyrosine kinase catalytic domain (De Meyts and Whittaker, 2002;Klarlund et al, 2003;Ward et al, 2008).…”

“…Despite the known biochemical and physiologic differences of these isoforms, changes in their expression levels have not been consistently found in patients with DM (Klarlund et al, 2003). Once insulin binds to the -subunit of the insulin receptor, it induces a conformational change in the receptor that subsequently leads to the stimulation of the intrinsic tyrosine kinase activity in the -subunits (Kanzaki, 2006;Klarlund et al, 2003;Stern, 1995). This results in the transfer of phosphate groups from ATP to several tyrosine residues on the insulin receptor itself as well as phosphorylation of cellular proteins such as insulin receptor substrate-1 (IRS-1) and Shc (Klarlund et al, 2003;Stern, 1995).…”