Cell surface receptors, when bound by their ligands, initiate intracellular signalling cascades that ultimately serve to modulate cell proliferation and growth, metabolism, survival and differentiation. Critical to the initiation and progression of these cascades are adaptor proteins such as the insulin receptor substrate (IRS) proteins. IRS proteins are a small family (IRS1–IRS6) of structurally related intracellular signalling adaptors that serve as scaffolding proteins, linking the activated receptor to their downstream effectors such as the phospatidylinositol-3′-kinase (PI3K) and Ras/Erk pathways.1 Originally identified as components of insulin receptor signalling, IRS factors are now known to serve as critical intermediates for the insulin-like growth factor I receptor (IGF-1R), as well as other receptor tyrosine kinases. The IRS family of adaptors has captured the attention of clinicians and scientists alike since they have been implicated in a number of human cancers.1 Given this critical role in both normal cell physiology and human pathologies, understanding how tissue-specific factors regulate their expression and thereby modulate IGF-1R signalling is of great importance. In this issue of Gut (see page 1250), Antonio Moschetta and colleagues present new findings on the intestinal localisation of IRS2 …