Following tyrosine phosphorylation, the insulin receptor substrate 1 and 2 (IRS-1 and IRS-2) can form a protein scaffolding for the assembly of a host of Src homology 2 (SH2) domain-containing proteins. IRS-1 tyrosine phosphorylation can occur through the activity of several cytokine and growth factor receptors such as interleukin (IL)-4, IL-9, interferon-gamma, in addition to the insulin and insulin-like growth factor 1 receptors. The scaffolding provided by IRS-1 and IRS-2 is necessary for insulin signal transduction across the cell membrane. IRS-1 tyrosine phosphorylation, and thus formation of the IRS scaffolding is inhibited by tumor necrosis factor (TNF), and this inhibition can itself be blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (TOR). TNF activity could also be blocked by inhibition of the Akt kinase and the PTEN tumor suppressor, suggesting that TNF impairs insulin signaling through IRS-1 by activation of the TOR signaling pathway.