TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance.

M. C. MUÑOZ; J. F. GIANI; M. A. MAYER; J. TOBLLI; D. TURYN; F. P. DOMINICI

JOURNAL OF ENDOCRINOLOGY

Año: 2009 vol. 201 p. 185 - 197

0022-0795

The IkBkinase-b (IKK-b)/nuclear factor-kB signalingpathway has been suggested to link inflammation withobesity and insulin resistance. In addition, angiotensin (Ang)II is able to induce insulin resistance and an inflammatory statethrough Ang II receptor type 1 (AT1R). Accordingly, weexamined whether inhibition of AT1R with irbesartan (IRB)can protect against the development of insulin resistance inobese Zucker rats (OZRs). IRB-treatment improved theinsulin-stimulated insulin receptor (IR) phosphorylationat tyrosine (Tyr) residues 1158, 1162, 1163 (involved inactivation of the IR kinase) and at Tyr972 (involvedin substrate recognition). AT1R blockade also originated adramatic increase in the phosphorylation of Akt and glycogensynthase kinase-3b. This was accompanied by a decrease inphosphorylation of IR on serine (Ser) 994, a residue thatseems to be implicated in the regulation of IR kinase inOZR. In this study, we demonstrated that Ser994 of IR is adirect substrate for TANK-binding kinase 1 (TBK1), a newmember of the IKK-related kinase family. TBK1 was found toco-immunoprecipitate with the IR, in the liver of OZRsupporting an in vivo association between the IR and TBK1.Interestingly, a marked increase in the association betweenTBK1 and the IR was found in the liver of OZR as well as inother models of insulin resistance/diabetes. Taken together,these findings suggest that TBK1 could be involved in theinsulin resistance mechanism related with IR Ser994phosphorylation in a genetic model of diabetes.