Insulin receptor substrate 1 and 2 (IRS1 and IRS2): What a tangled web we weave

The insulin receptor is a transmembrane tyrosine kinase that is essential for mediating multiple intracellular signalling cascades that lead ultimately to the biological actions of insulin. Tyrosine phosphorylation of the cytosolic proteins insulin receptor substrate 1 and 2 (IRS1 and IRS2) produces protein 'scaffolding' for the assembly of effector proteins containing Src homology 2 (SH2) domains, thereby generating multisubunit signalling complexes. Although IRS1 was originally isolated as a specific insulin receptor substrate, both IRS1 and IRS2 appear to play a broader role, functioning also as proximal substrates in growth hormone and cytokine receptor signalling. Current data establish IRS1 and IRS2 as critical effectors integrating various cell-type-specific signals into distinct, but overlapping, biological responses.