Growth factor triggering of protein tyrosine kinase receptors induces signals that cascade to the nucleus activating mitogenic, as well as other, responses. Critical components of this process include adapter proteins such as Shc and IRS-1 that lack detectable catalytic activity. These are immediate substrates of receptor tyrosine kinase activity and serve to physically link activated receptors to downstream signaling components. Whereas Shc has been implicated in signaling by diverse receptor families, IRS-1 serves primarily as the major insulin receptor substrate (4-7). Shc also participates in insulin signaling by linking the insulin receptor to Ras by forming complexes with the adapter protein GRB2 and Sos independently of IRS-1. A protein immunologically related to IRS-1, originally designated 4PS and now known as IRS-2, was shown to become highly tyrosine phosphorylated in response to IL-4 or IGF-1 in cells lacking IRS-1. An additional member of this family of signaling intermediates, Shb, is a SH2-containing protein with characteristic proline-rich domains.