title: Insulin-induced mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) attenuates insulin-stimulated MAP kinase activity: a mechanism for the feedback inhibition of insulin signaling.
abstract: Insulin signaling involves the transient activation/inactivation of various proteins by a cycle of phosphorylation/dephosphorylation. This dynamic process is regulated by the action of protein kinases and protein phosphatases. One family of protein kinases that is important in insulin signaling is the mitogen-activated protein (MAP) kinases, whose action is reversed by specific MAP kinase phosphatases (MKPs). Insulin stimulation of Hirc B cells overexpressing the human insulin receptor resulted in increased MKP-1 mRNA levels. MKP-1 mRNA increased in a dose-dependent manner to a maximum of 3- to 4-fold over basal levels within 30 min, followed by a gradual return to basal. The mRNA induction did not require the continuous presence of insulin. The induction of MKP-1 protein synthesis followed MKP-1 mRNA induction; MKP-1 protein was maximally expressed after 120 min of insulin stimulation. MKP-1 mRNA induction by insulin required insulin receptor tyrosine kinase activity, since overexpression of an altered insulin receptor with impaired intrinsic tyrosine kinase activity prevented mRNA induction. Forskolin, (Bu)2-cAMP, 8-bromo-cAMP, and 8-(4-chlorophenylthio)-cAMP increased the MKP-1 mRNA content moderately above basal. These agents also augmented the insulin-stimulated expression of MKP-1 mRNA. However, in some cases the increase in MKP-1 mRNA expression was less than additive. Nevertheless, these results indicate that multiple signaling motifs might regulate MKP-1 expression and suggest another mechanism for the attenuation of insulin-stimulated MAP kinase activity by cAMP. Overexpression of MKP-1 in Hirc B cells inhibited both insulin-stimulated MAP kinase activity and MAP kinase-dependent gene transcription. The results of these studies led us to conclude that insulin regulates MKP-1 and strongly suggest that MKP-1 acts as a negative regulator of insulin signaling.
authors.affiliation: The Department of Physiology, Tulane University Medical Center, New Orleans, Louisiana 70112-2699, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Kusari
authors.forename: J
authors.initials: J
authors.lastname: Byon
authors.forename: D
authors.initials: D
authors.lastname: Bandyopadhyay
authors.forename: K A
authors.initials: KA
authors.lastname: Kenner
authors.forename: J
authors.initials: J
authors.lastname: Kusari
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D007328:Insulin; D012333:RNA, Messenger; D000242:Cyclic AMP; D011972:Receptor, Insulin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases