Insulin receptor substrates (IRS), the major intracellular substrates of the insulin receptor (IR), are adaptor proteins that transduce signals from the IR to downstream effectors that are important for the biological effect of insulin (1-2). After insulin stimulation, IRS proteins are rapidly phosphorylated on multiple tyrosine residues. Once phosphorylated, IRS proteins bind and activate Grb-2, SHP2 and the PI3-K p85 subunit (2-3). Sequences of IRS-2 and IRS-1 reveal a highly conserved amino terminus containing a pleckstrin-homology domain and a phosphotyrosine-binding domain, and a poorly conserved carboxy terminus containing several tyrosine phosphorylation motifs. IRS-2 is expressed in many cells, including tissues from IRS-1-/- mice, and may be essential for signaling by several receptor systems such as insulin and cytokine (1).