The Insulin Receptor Substrate (IRS) proteins are key players in insulin signal transduction and are the best studied targets of the insulin receptor. Ser/Thr phosphorylation of IRS proteins negatively modulates insulin signaling; therefore, the identification of IRS kinases and their target Ser phosphorylation sites is of physiological importance. Here we show that in Fao rat hepatoma cells, the IB kinase ␤ (IKK␤) is an IRS-1 kinase activated by selected inducers of insulin resistance, including sphingomyelinase, ceramide, and free fatty acids. Moreover, IKK␤ shares a repertoire of seven potential target sites on IRS-1 with protein kinase C (PKC), an IRS-1 kinase activated both by insulin and by inducers of insulin resistance. We further show that mutation of these seven sites (Ser-265, Ser-302, Ser-325, Ser-336, Ser-358, Ser-407, and Ser-408) confers protection from the action of IKK␤ and PKC when they are overexpressed in Fao cells or primary hepatocytes. This enables the mutated IRS proteins to better propagate insulin signaling. These findings suggest that insulin-stimulated IRS kinases such as PKC overlap with IRS kinases triggered by inducers of insulin resistance, such as IKK␤, to phosphorylate IRS-1 on common Ser sites. The Insulin Receptor Substrate (IRS)2 proteins are key players in insulin signal transduction and are the best studied targets of the insulin receptor (reviewed in Refs. 1 and 2). They contain a conserved pleckstrin homology domain, located at the amino terminus, that serves to anchor the IRS proteins to membrane phosphoinositides in close proximity to the insulin receptor (3). The pleckstrin homology domain is flanked by a P-Tyr binding (PTB) domain that functions as a binding site to the NPXY motif at the juxtamembrane domain of the insulin receptor (4). The C-terminal region of IRS proteins is poorly conserved. It contains multiple Tyr phosphorylation motifs that serve as a signaling scaffold, providing a docking interface for Src homology 2 domain-containing proteins like the p85␣ regulatory subunit of phosphatidylinositol 3-kinase, Grb2, Nck, Crk, Fyn, and SHP-2, which further propagate the metabolic and growth-promoting effects of insulin (5, 6).IRS-1 contains 232 Ser/Thr residues (7), many of which could be subjected to phosphorylation. Ser/Thr phosphorylation has been increasingly recognized as a negative counterbalance to positive IRS signaling through tyrosine phosphorylation (1). Ser/Thr phosphorylation reduces IRS-1 ability to undergo Tyr phosphorylation by the insulin receptor kinase and might serve as a physiological negative feedback control mechanism to turn off insulin's signaling by uncoupling the IRS proteins from their upstream and downstream effectors (8 -10). Furthermore, this mechanism can be utilized by inducers of insulin resistance under pathological conditions. Thus, Ser/Thr phosphorylation could be a generalized mechanism for insulin resistance (1). Several candidate Ser residues were identified as potential targets for IRS-1 kinases. These include Ser-24 (11)...

Not infrequently, gastric volvulus in children fails to exhibit the full gamut of signs and symptoms such as abdominal distension, vomiting, pain, and retching. For this, as well as for other stated reasons, symptomatic gastric volvulus in infancy and childhood may not be as rare as is commonly assumed.

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