The Insulin Receptor (IR) is synthesized as a single polypeptide, which is subsequently cleaved to generate an extracellular α chain and a transmembrane and intracellular β chain, tethered together by disulfide bonds. The β chain has multiple tyrosine phosphorylation sites, including three autophosphorylation sites at its activation loop. Insulin stimulates the signaling cascade by binding to the insulin receptor through its extracellular α subunits. This stimulates the tyrosine kinase activity of the β subunits of the receptor. The receptor then autophosphorylates itself and phosphorylates the IRS (Insulin Receptor Substrate) proteins that are very important modulators of insulin signaling. Phosphorylated IRS, in turn, interacts with several downstream effectors of insulin signaling, including PI3 Kinase p85, GRB2, SHP2, Nck, Crk, and Fyn. The overall structure of the IR is highly homologous to the IGF-I Receptor, except in their c-termini, where the two proteins diverge somewhat. Insulin signaling is highly dependent on the PI3 Kinase pathway and Akt, which appear to mediate the functions of insulin.