Corresponding author: Professor RM Denton, University of Bristol, Department of Biochemistry, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK multiple tyrosine residues which form SH2 binding sites; proline-rich motifs to engage SH3motifs or WW domains; and serine/threonine rich regions which may regulate overall function through other protein-protein interactions or phosphorylation events. Other docking proteins have been identified including Shc, p130cas and sin. Shc is composed of an NH2-terminal PTB domain, a COOH-terminal SH2 domain, an intervening proline-rich motif, and a few tyrosine phosphorylation sites, one of which engages the SH2 domain of Grb-2. The PTB and SH2 domains provide Shc with considerable promiscuity in its interplay with activated receptors, but without a PH domain commonly found in IRS proteins, Shc is a relatively weak insulin receptor substrate. The p130cas and sin proteins posses SH3 domains which couple these docking proteins to Src kinase but precludes their interaction with the insulin receptor. The future holds considerable promise for the discovery of new docking proteins to coordinate signalling from the insulin and other receptors. What signalling advantages do the IRS proteins provide? Firstly, IRS proteins provide a mechanism for signal amplification by eliminating the stoichiometric restraints encountered by receptors which directly recruit SH2 proteins to their autophosphorylation sites. Secondly, IRS proteins may dissociate the intracellular signalling complex from the endocytic pathways of the activated receptor. Thirdly, the interaction of a single insulin receptor with multiple IRS protein isoforms expands the repertoire of signalling pathways that can be regulated. Finally, the use of shared IRS proteins by multiple receptors provides a mechanism to integrate several receptor systems through a single complex. The major mechanism which generates signals by activated IRS-proteins is the binding of SH2 proteins to tyrosine phosphorylated proteins including phosphatidylinositol-3 kinase (p85a/p55a, p85b, p55pik), Grb-2, SHP-2, fyn, nck and crk. The phosphatidylinositol-3 kinase and SHP-2 are enzymes that are activated during association with IRS-1; nck, crk and Grb-2 are adapter molecules which link activated IRS proteins to various signalling pathways including Ras. In addition however, IRS proteins may mediate additional signals which depend upon serine phosphorylation or other protein-protein interactions. In parallel with the work described above, a large group of cytokines and growth factors also engage and phosphorylate IRS proteins, including IGF-1 and growth hormone, members of the interleukin (IL)-2 family of cytokines (IL-2, IL-4, IL-9, IL-13 and IL-15), IL-6 related cytokines (oncostarin M. OSM, leukocyte inhibitory factor LIF and leptin) and interferons. This crosstalk raises the possibility that disruption of insulin signalling and the subsequent alteration of other signalling systems may contribute to disease.