The circulating peptide hormones insulin (INS, P01308) and the related insulin-like growth factors (IGF) activate Class II receptor tyrosine kinases [4], to evoke cellular responses, mediated through multiple intracellular adaptor proteins. Exceptionally amongst the catalytic receptors, the functional receptor in the insulin receptor family is derived from a single gene product, cleaved post-translationally into two peptides, which then cross-link via disulphide bridges to form a heterotetramer. Intriguingly, the endogenous peptide ligands are formed in a parallel fashion with post-translational processing producing a heterodimer linked by disulphide bridges. Signalling through the receptors is mediated through a rapid autophosphorylation event at intracellular tyrosine residues, followed by recruitment of multiple adaptor proteins, notably IRS1 (P35568), IRS2 (Q9Y4H2), SHC1 (P29353), GRB2 (P62993) and SOS1 (Q07889).

Serum levels of free IGFs are kept low by the action of IGF binding proteins (IGFBP1-5, P08833, P18065, P17936, P22692, P24593), which sequester the IGFs; overexpression of IGFBPs may induce apoptosis, while IGFBP levels are also altered in some cancers.

There is evidence for low potency binding and activation of insulin receptors by IGF1. IGF2 also binds and activates the cation-independent mannose 6-phosphate receptor (also known as the insulin-like growth factor 2 receptor; IGF2R; P11717), which lacks classical signalling capacity and appears to subserve a trafficking role [6]. INSRR, which has a much more discrete localization, being predominant in the kidney [5], currently lacks a cognate ligand or evidence for functional impact.

Antibodies targetting IGF1, IGF2 and the extracellular portion of the IGF1 receptor are in clinical trials.

PQ401 inhibits the insulin-like growth factor receptor [5], while BMS-536924 inhibits both the insulin receptor and the insulin-like growth factor receptor [9].

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