Protein kinase D activation stimulates the transcription of the insulin receptor gene

Our previous studies proved that berberine (BBR) up-regulates the insulin receptor (InsR) gene by stimulating its promoter and calphostin C blocks this effect. Here, the present study was designed to discover the specific kinase isoform(s) used by berberine. In the blocking experiment, we found that Go6976, a kinase inhibitor that potently inhibit PKC mu/protein kinase D 1 (PKD1), effectively and specifically reduced the activity of BBR on InsR. PKD1/PKC mu is a member of the PKD family that also covers PKD2 and PKD3/PKC nu with high homology. The role of PKD1 in InsR expression was also proved by using another PKD-activator oligomycin. In the RNA interference experiment, we found that the effects of BBR on InsR expression and on cellular glucose consumption were partially eliminated by silencing any one of the three PKDs and were totally abolished by silencing all of them. BBR enhanced the PKD1 catalytic activity, but not its expression. Along with BBR treatment, PKD1 ser916 autophosphorylation was increased time- and dose-dependently, indicating an activation of PKD1 by BBR. BBR also induces PKD1 translocation from cytosol-to-plasma membrane, further verifying the activation of PKD1. These results suggest that the PKD family is involved in the transcriptional regulation of the InsR gene; we consider it to be a potential new target to discover drugs for sugar-related disorders in the future. (C) 2010 Elsevier Ireland Ltd. All rights reserved.