What does insulin bind to

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Gaps remain in our understanding of the precise molecular mechanisms by which insulin regulates glucose uptake in fat and muscle cells. Recent evidence suggests that insulin action involves multiple pathways, each compartmentalized in discrete domains.

Upon activation, the receptor catalyzes the tyrosine phosphorylation of a number of substrates. One family of these, the insulin receptor substrate IRS proteins, initiates activation of the phosphatidylinositol 3-kinase pathway, resulting in stimulation of protein kinases such as Akt and atypical protein kinase C. The receptor also phosphorylates the adapter protein APS, resulting in the activation of the G protein TC10, which resides in lipid rafts.

TC10 can influence a number of cellular processes, including changes in the actin cytoskeleton, recruitment of effectors such as the adapter protein CIP4, and assembly of the exocyst complex. These pathways converge to control the recycling of the facilitative glucose transporter Glut4. Insulin is the most potent physiological anabolic agent known, promoting the storage and synthesis of lipids, protein, and carbohydrates and inhibiting their breakdown and release into the circulation 1.

The first step by which insulin increases energy storage or utilization involves the regulated transport of glucose into the cell, mediated by the facilitative glucose transporter Glut4. Insulin increases glucose uptake mainly by enriching the concentration of Glut4 proteins at the plasma membrane, rather than by increasing the intrinsic activity of the transporter 2 , 3.

The cellular location of Glut4 is governed by a process of regulated recycling, in which endocytosis, sorting into specialized vesicles, exocytosis, tethering, docking, and fusion of the protein are tightly regulated. We discuss here the molecular basis for these events and the signaling pathways by which they are controlled.

In the absence of insulin, Glut4 slowly recycles between the plasma membrane and vesicular compartments within the cell, where most of the Glut4 resides. Insulin stimulates the translocation of a pool of Glut4 to the plasma membrane, through a process of targeted exocytosis 4 , 5 Figure 1. At the same time, Glut4 endocytosis is attenuated 6 , 7. Thus, the rate of glucose transport into fat and muscle cells is governed by the concentration of Glut4 at the cell surface and the duration for which the protein is maintained at this site.

Recycling of Glut4. The cellular location of Glut4 is governed by a process of regulated recycling, in which the endocytosis, sorting into specialized vesicles, exocytosis, tethering, docking, and fusion of the protein are tightly regulated. Insulin stimulates the translocation of a pool of Glut4 to the plasma membrane, through a process of targeted exocytosis. The microtubule network and actin cytoskeleton play a role in Glut4 trafficking, either by linking signaling components or by directing movement of vesicles from the perinuclear region to the plasma membrane in response to insulin.

Once at the plasma membrane, the Glut4 vesicles dock and fuse, allowing for extracellular exposure of the transporter. There is substantial evidence that Glut4 exists in specialized vesicles sequestered within the cell, but the precise intracellular location and trafficking pathways of these vesicles are unclear.

Following internalization, Glut4 is localized into tubulovesicular and vesicular structures that are biochemically distinct from but possibly interacting with the recycling endosomal network 8. In adipocytes, these vesicles are retained in a perinuclear region in the cell via an unknown mechanism that might involve a tethering protein 9 or continuous futile recycling Consistent with these data, ablation of transferrin receptor containing endosomes does not impair insulin-stimulated Glut4 translocation Cortical actin is required for Glut4 translocation to the plasma membrane in response to insulin 13 — 15 , which is regulated by TC10 see Insulin Signaling From Lipid Rafts, below 14 , In addition, microtubule motor proteins kinesin KIF5b and KIF3 have been shown to facilitate insulin-stimulated Glut4 transit to the plasma membrane 17 , Thus, it is likely that molecular motors move the Glut4 vesicles along tracks involving the microtubule and actin cytoskeletons, which may undergo dynamic remodeling in response to insulin.

Although these SNARE interactions are essential, none of the core proteins appear to be direct targets of insulin action. On the other hand, several important SNARE accessory proteins such as Munc18c, Synip, and NSF N -ethylmaleimide sensitive factor may be involved in the control of Glut4 docking and fusion events and might be targets of insulin action 19 — In fact, Munc18c heterozygous knockout mice are less insulin sensitive than wild-type mice, with reduced insulin-stimulated Glut4 translocation in skeletal muscle However, opposite results were seen with isolated adipocytes from homozygous Munc18c knockout mice The receptor also undergoes autophosphorylation at other tyrosine residues in the juxtamembrane regions and intracellular tail Figure 2.

Upon phosphorylation, these substrates interact with a series of effector or adapter molecules containing Src homology 2 SH2 domains that specifically recognize different phosphotyrosine motifs. Among these substrates, the best characterized are the IRS family of proteins. Activation of insulin receptor. The receptor also undergoes autophosphorylation at other tyrosine residues in the juxtamembrane regions and intracellular tail The activated IR then phosphorylates tyrosine residues on intracellular substrates.

IRS-1 knockout mice are growth retarded and do not appear to develop diabetes, but are insulin resistant in peripheral tissues, with defective glucose tolerance The stimulation of glucose uptake by insulin is mediated by phosphatidylinositol PI 3-kinase-dependent and -independent pathways 3 , Upon tyrosine phosphorylation, IRS proteins interact with the p85 regulatory subunit of PI 3-kinase, leading to the activation of the enzyme and its targeting to the plasma membrane.

The enzyme generates the lipid product phosphatidylinositol 3,4,5-trisphosphate PIP 3 , which regulates the localization and activity of numerous proteins PI 3-kinase plays an essential role in glucose uptake and Glut4 translocation. Inhibition of the enzyme with pharmacological inhibitors such as wortmannin completely blocks the stimulation of glucose uptake by insulin Additionally, overexpression of dominant-interfering forms of PI 3-kinase can block glucose uptake and Glut4 translocation, and overexpression of constitutively active forms can partially mimic insulin action 33 , Zakova, E.

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