The IRS-Signalling System in Insulin and Cytokine Action [and Discussion]

Morris F. White , P. Cohen

Abstract

IRS-signalling proteins are engaged and phosphorylated on tyrosine residues by the receptors for insulin and IGF-1, and various classes of cytokine receptors, including IL-4, IL-9, and IL-13; IFN<latex>$\alpha $</latex>/<latex>$\beta $</latex> and IFN<latex>$\gamma $</latex>; and growth hormone and LIF. IRS-proteins provide an interface between these receptors and signalling proteins which contain Src homology-2 domains (SH2-proteins). The recent identification of IRS-2 provides new insight into the modular structure and function of the IRS-proteins. The IRS-proteins provide a means for signal amplification by eliminating the stoichiometric constraints encountered by most receptors which directly recruit SH2-proteins to their autophosphorylation sites. Moreover, IRS-proteins dissociate the intracellular signalling complex from the endocytic pathways of the activated receptor. The shared use of IRS-proteins by multiple receptors is likely to reveal important connections between various hormones and cytokines that were previously unrecognized, or observed but unexplained. The existence of additional signalling molecules based on the IRS-paradigm is likely.