title: Insulin activates RSK (p90 ribosomal S6 kinase) to trigger a new negative feedback loop that regulates insulin signaling for glucose metabolism.
abstract: We previously demonstrated that the mTORC1/S6K1 pathway is activated by insulin and nutrient overload (e.g. amino acids (AA)), which leads to the inhibition of the PI3K/Akt pathway via the inhibitory serine phosphorylation of IRS-1, notably on serine 1101 (Ser-1101). However, even in the absence of AA, insulin can still promote IRS-1 Ser-1101 phosphorylation by other kinases that remain to be fully characterized. Here, we describe a new negative regulator of IRS-1, the p90 ribosomal S6 kinase (RSK). Computational analyses revealed that Ser-1101 within IRS-1 falls into the consensus motif of RSK. Moreover, recombinant RSK phosphorylated IRS-1 C-terminal fragment on Ser-1101, which was prevented by mutations of this site or when a kinase-inactive mutant of RSK was used. Using antibodies directed toward the phosphorylation sites located in the activation segment of RSK (Ser-221 or Ser-380), we found that insulin activates RSK in L6 myocytes in the absence of AA overload. Inhibition of RSK using either the pharmacological inhibitor BI-D1870 or after adenoviral expression of a dominant negative RSK1 mutant (RSK1-DN) showed that RSK selectively phosphorylates IRS-1 on Ser-1101. Accordingly, expression of the RSK1-DN mutant in L6 myocytes and FAO hepatic cells improved insulin action on glucose uptake and glucose production, respectively. Furthermore, RSK1 inhibition prevented insulin resistance in L6 myocytes chronically exposed to high glucose and high insulin. These results show that RSK is a novel regulator of insulin signaling and glucose metabolism and a potential mediator of insulin resistance, notably through the negative phosphorylation of IRS-1 on Ser-1101.
authors.affiliation: From the Quebec Heart and Lung Institute, Laval University, 2705 Chemin Ste-Foy, Ste-Foy (Quebec) G1V4G5, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Smadja-Lamère
authors.forename: Michael
authors.initials: M
authors.lastname: Shum
authors.forename: Paul
authors.initials: P
authors.lastname: Déléris
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Roux
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Abe
authors.forename: André
authors.initials: A
authors.lastname: Marette
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism; D020125:Mutation, Missense; D010766:Phosphorylation / Q000502:physiology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D005947:Glucose
keywords: Akt; Glucose Metabolism; Hepatocyte; IRS-1; Insulin Resistance; Muscle; Rsk; Serine Phosphorylation
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