Figure 1

General scheme of insulin signaling. Insulin binding to its receptor activates the receptor tyrosine kinase activity. This leads to autophosphorylation of the receptor and recruitment and phosphorylation of insulin receptor substrate (IRS) proteins. Subsequently, other signaling molecules such as PI3-kinase (PI3K) and GRB2 are recruited, which leads to the activation of the Akt signaling pathway (which mediates many metabolic effects) and the MAP kinase pathway (which mediates cell proliferation), respectively. Insulin binding also leads to receptor internalization into endosomes. From endosomes, receptors can recycle back to the plasma membrane or traffic via multivesicular bodies to the lysosome for degradation. Phosphorylated IRS and the IRS-PI3K complex are signaling molecules that can be inactivated by degradation through the ubiquitin proteasome system. Receptor internalization and trafficking between the endosome and lysosome has been shown to be dependent on ubiquitylation for other receptor tyrosine kinases, but the requirement for UBIQ (ubiquitin) in the case of the insulin receptor remains speculative. In some adipocyte cell lines, the ubiquitin protein ligase CBLB (Cbl-b) has been implicated in mediating translocation of the GTR4 (GLUT4) glucose transporter to the plasma membrane via a RHOQ (Tc10)-dependent pathway.