title: TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance.
abstract: The I kappaB kinase-beta (IKK-beta)/nuclear factor-kappaB signaling pathway has been suggested to link inflammation with obesity and insulin resistance. In addition, angiotensin (Ang) II is able to induce insulin resistance and an inflammatory state through Ang II receptor type 1 (AT1R). Accordingly, we examined whether inhibition of AT1R with irbesartan (IRB) can protect against the development of insulin resistance in obese Zucker rats (OZRs). IRB-treatment improved the insulin-stimulated insulin receptor (IR) phosphorylation at tyrosine (Tyr) residues 1158, 1162, 1163 (involved in activation of the IR kinase) and at Tyr972 (involved in substrate recognition). AT1R blockade also originated a dramatic increase in the phosphorylation of Akt and glycogen synthase kinase-3beta. This was accompanied by a decrease in phosphorylation of IR on serine (Ser) 994, a residue that seems to be implicated in the regulation of IR kinase in OZR. In this study, we demonstrated that Ser994 of IR is a direct substrate for TANK-binding kinase 1 (TBK1), a new member of the IKK-related kinase family. TBK1 was found to co-immunoprecipitate with the IR, in the liver of OZR supporting an in vivo association between the IR and TBK1. Interestingly, a marked increase in the association between TBK1 and the IR was found in the liver of OZR as well as in other models of insulin resistance/diabetes. Taken together, these findings suggest that TBK1 could be involved in the insulin resistance mechanism related with IR Ser994 phosphorylation in a genetic model of diabetes.
authors.affiliation: Instituto de Química y Fisicoquímica Biológicas (UBA-CONICET), IQUIFIB Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, Capital Federal, 1113 Buenos Aires, Argentina.
authors.forename: Marina C
authors.initials: MC
authors.lastname: Muñoz
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Giani
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Mayer
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Toblli
authors.forename: Daniel
authors.initials: D
authors.lastname: Turyn
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Dominici
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism
chemical_list: D012694:Serine; C498588:Tbk1 protein, mouse; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases