Negative feedback regulation of IRS-1. Serine residues that are phosphorylated in IRS-1 and the kinases that target these sites are indicated. Kinases shown in purple mediate signaling events that impede IRS-1 localization to the membrane or upstream receptors by disrupting PH and/or PTB domain function. Kinases shown in orange mediate signaling events that interfere with PI3K recruitment and activation. Kinases shown in pink mediate signaling events that result in phosphorylation of S789. Kinases that initiate signaling events that result in phosphorylation of S1223 and interfere with SHP-2 binding are unknown (yellow). Exogenous stimuli that have been implicated in cancer and that can activate kinases to regulate IRS-1 serine phosphorylation are indicated.