IndraLab

"Here we report that glycogen synthase kinase 3 (GSK-3) is capable of phosphorylating IRS-1 and that this modification converts IRS-1 into an inhibitor of IR tyrosine kinase activity in vitro."

"Insulin affects cells through binding to its receptor on the surface of insulin-responsive cells. The stimulated insulin receptor phosphorylates itself and several substrates, including members of the insulin receptor substrate (IRS) family, thus initiating downstream signaling events (32, 33). The inhibition of signaling downstream of the insulin receptor is a primary mechanism through which inflammatory signaling leads to insulin resistance. Exposure of cells to TNF-a or elevated levels of free fatty acids stimulates inhibitory phosphorylation of serine residues of IRS-1"

"The 3 members of the JNK group of serine/threonine kinases, JNK-1, -2, and -3, JNK has recently emerged as a central metabolic regulator, playing an important role in the development of insulin resistance in obesity In response to stimuli such as ER stress, cytokines, and fatty acids, JNK is activated, whereupon it associates with and phosphorylates IRS-1 on Ser307, impairing insulin action"

"Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639"

"S6K was shown to directly phosphorylate IRS-1 to inhibit phosphatidylinositol-3-kinase (PI3K) and Akt activation (Harrington ete al, 2004)."