Insulin Receptor Signaling

Insulin is an anabolic hormone essential for maintenance of whole-body glucose homeostasis, growth and development. Insulin regulates glucose homeostasis at many sites. It reduces hepatic glucose output via decreased gluconeogenesis and glycogenolysis and increases the rate of glucose uptake into striated muscle and adipose tissue. Insulin also profoundly affects lipid metabolism, increasing lipid synthesis in liver and fat cells, and controlling fatty acid release from triglycerides in fat and muscle.Insulin action is initiated by binding to its cell surface receptor which is an α2β2 heterotetrameric complex. Once activated, the insulin receptor tyrosine phosphorylates a number of important proximal substrates including members of the insulin receptor substrate family (IRS1/2/3/4), the SHC adapter protein isoforms, Grb2-associated binder-1(GAB-1) and the adapter protein CBL. Tyrosine phosphorylation of the IRS proteins creates recognition sites for additional effector molecules containing Src homology 2 (SH2) domains. These include the small adapter proteins GRB2 and NCK, which can trigger the RAS/Mitogen activated protein kinase (MAPK) pathway leading to cell growth. However, one of the most important targets of insulin receptor mediated phosphorylation is phosphatidylinositol 3-kinase (PI 3K).Two classes of serine/threonine kinases are known to act downstream of PI 3-kinase, namely the serine/threonine kinase Akt, also known as protein kinase B (PKB), and the atypical protein kinase C isoforms zeta and gamma (PKCζ/γ). The activation of PKB results in the phosphorylation and activation of cyclic nucleotide phosphodiesterase (PDE) which is a regulator of cyclic adenosine monophosphate cAMP levels. As a result of the lower levels of cAMP, hormone sensitive lipase (HPL) is inhibited, thus decreasing lipolysis. AKT also inhibits the activity of Glycogen synthase kinase 3 (GSK3). This relieves the inhibition of ATP citrate lyase, thereby promoting fatty acid synthesis. In addition to its effects on lipid homeostasis, Insulin activated PKB phosphorylates and inhibits the tuberous sclerosis complex (TSC), which in turn is an inhibitor of mammalian target of rapamycin (mTOR) - a central regulator of protein synthesis. The inhibition of TSC thus leads to an enhancement of protein synthesis. In addition, insulin activation results in the translocation of PKB to the nucleus. where it regulates members of the Fork head family of transcription factors and promotes cell survival. In the cytoplasm PKB phosphorylates and inactivates components of the apoptotic machinery, including BAD. Thus, the PI3K/PKB pathway is an important component of insulin signaling.One of the fundamental actions of insulin is to stimulate the uptake of glucose from blood into tissues. This uptake occurs via glucose transporters (GLUT). The most important GLUT in insulin action is GLUT4, which is localized in endosomal vesicles and is induced by insulin to translocate with the vesicle to the plasma membrane. Several proteins have been identified in association with the GLUT4 compartment and are known to be associated with GLUT4 at the plasma membrane. These include the vesicle-associated membrane protein 2 (VAMP2), which interacts with a target membrane SNAP receptor (t-SNARE) for e.g. syntaxin. Insulin mediated activation of PKC ζ induces serine phosphorylation of VAMP2 in the GLUT4 compartment, which in turn promotes GLUT4 vesicle transport to the plasma membrane and thereby increases glucose uptake.This pathway highlights the key components of insulin signaling.