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Falguni Das

Falguni Das

University of Texas Health Science Center, USA

Title: Ser-660 Phosphorylation of Protein Kinase C beta II ( pkcβii) by mammalian target of rapamycin complex 2 (mtorc2) Regulates High Glucose (HG)-induced Mesangial Cell Hypertrophy

Biography

Biography: Falguni Das

Abstract

Protein kinase C beta II (PKCβII) has been implicated in diabetic nephropathy (DN). Mesangial cell (MC) hypertrophy is a pathologic feature of DN. PKCβII undergoes phosphorylation at the hydrophobic motif site Ser-660 for its activity. We have shown that mTOR complex 1 (C1) regulates MC hypertrophy. How activation of PKCβII by Ser-660 phosphorylation fits into mTOR signaling to control MC hypertrophy is not known. HG significantly increased phosphorylation of PKCβII at Ser-660 in a PI 3 kinase dependent manner. siRNAs against PKCβII, dominant negative PKCβII and non-phosphorylatable mutant of PKCβII, PKCβIIS660A, blocked mTORC1 activity due to lack of PRAS40 phosphorylation, resulting in significant inhibition of HG induced MC protein synthesis and hypertrophy. Also, PKCβIIS660A attenuated phosphorylation of Akt at Ser-473, a putative mTOR complex 2 (C2) site. Specific inhibition of mTORC2 by shRNAs against rictor or Sin1, two exclusive and required components for its activity, suppressed HG induced phosphorylation of PKCβII Ser-660 and Akt Ser-473, resulting in attenuation of mTORC1 activity leading to inhibition of MC hypertrophy. Constitutively active (CA) Akt or CA mTORC1 reversed shRictor or shSin1 mediated inhibition of HG induced MC hypertrophy. Furthermore, CA PKCβII reversed the shRictor or shSin1 induced inhibition of HG stimulated Akt Ser-473 phosphorylation and MC hypertrophy. Finally, we show increased phosphorylation of PKCβII Ser660, PRAS40 and Akt Ser-473 in association with activation of mTORC1 in renal cortices of OVE26 mice with type-1 diabetes. These results provide the first evidence that HG induced activation of mTORC2 phosphorylates and activates PKCβII to increase the phosphorylation of Akt at Ser-473 to finally activate mTORC1 to induce MC hypertrophy. Thus, we uncover a specific role of mTORC2 for Akt/mTORC1 activation via PKCβII Ser-660 phosphorylation.