The insulin receptor substrate-1 protein (IRS 1) is a cytoplasmic docking protein that functions as a signaling intermediate downstream of activated cell surface receptors such as the insulin receptor. IRS-1 contains a pleckstrin homology (PH, 12-113, human) and a phosphotyrosine binding (PTB, 160-263, human) domain at the N-terminus that target IRS-1 to the insulin receptor. The C-terminus domain contains a number of tyrosine phosphorylation motifs that are phosphorylated by the insulin receptor. The IRS-1 also contains several serine phosphorylation sites that have been linked to both the sensitivity of the IRS-1 to tyrosine phosphorylation by insulin and to insulin resistance. Phosphorylation of the IRS-1 on serine residues have been shown to decrease binding of IRS-1 to the insulin receptor, decrease tyrosine phosphorylation and increase the degradation of IRS 1 (Biochimie, 87:99-109, 2005).

Phosphorylation of serine 24 by protein kinase C alpha (PKC alpha) alters PH domain function, regulates phosphoinositide binding and the intracellular localization of the PH domain (Molecular Endocrinology, 20:1838-1852, 2006). It also has been shown that mouse Pelle-like Kinase/Interleukin-1 receptor associated Kinase (mPLK/IRAK) can phosphorylate the IRS-1 on serine 24 leading to impairment in PI 3-kinase-dependent insulin signaling (JBC, 280; 23173-23183, 2005).

Phosphorylation of the IRS-1 (human) on serine 303, 307, 312 and 323 modulates the ability of the insulin receptor to phosphorylate tyrosine residues on IRS-1. Protein kinase C delta (PKC delta) phosphorylates serine 307 and 323 (Biochem. J., 378; 105-116, 2004). Inhibitors of phosphatidylinositol 3-kinase (PI 3-Kinase) and mammalian target of rapamycin (mTOR) blocked the phosphorylation of serine 312 and also blocked the insulin stimulated increase in serine 312 phosphorylation (JBC, 278; 8199-8211, 2003). Leptin has been shown to down-regulate insulin action through a Jak-2 and PKC delta pathway. Leptin stimulates the phosphorylation of serine 323 which results in a decrease in coupling of IRS-1 to the insulin receptor (The FASEB J, 20; 1206-1208, 2006).

Phosphorylation of the IRS-1 on serine 413 (human) results in the dissociation of the IRS-1 from the insulin receptor. Serine 413 is located in a region of the IRS-1 (365-430) that is a main insulin stimulated serine phosphorylation domain. Serine 413 plays a negative regulatory role in IRS-1 function and insulin action (Mol. Cell. Biol., 24; 9668-9681, 2004).

Phosphorylation of tyrosine 612 (human) and tyrosine 632 (human) is important for binding and activation of phosphatidylinositol 3-kinase. Phosphorylation of serine 616 (human) and serine 636 (human), which is located near the Src-homology 2-binding motifs, may prevent tyrosine phosphorylation by the insulin receptor, p85 recruitment or inracellular complex formation (JBC, 272; 31400-31406, 1997; Biochimie 87; 99-109, 2005; Cell Cycle, 6; 631-637, 2007).

Phosphorylation of serine 1101 (human) by protein kinase theta (PKC theta) blocks tyrosine phosphorylation and downstream activation of the Akt pathway (Journal Biological Chemistry, 279: 45304-45307, 2004)