GET THE APP

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
..

Journal of Nephrology & Therapeutics

ISSN: 2161-0959

Open Access

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


12th Annual Conference on Nephrology & Urology

JULY 06-07, 2017 KUALA LUMPUR, MALAYSIA

F Das, N Ghosh Choudhury, M Mariappan, B S Kasinath and G Ghosh Choudhury

University of Texas Health Science Center, USA

Posters & Accepted Abstracts: J Nephrol Ther

Abstract :

Protein kinase C beta II (PKC?²II) has been implicated in diabetic nephropathy (DN). Mesangial cell (MC) hypertrophy is a pathologic feature of DN. PKC?²II 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 PKC?²II by Ser-660 phosphorylation fits into mTOR signaling to control MC hypertrophy is not known. HG significantly increased phosphorylation of PKC?²II at Ser-660 in a PI 3 kinase-dependent manner. siRNAs against PKC?²II, dominant negative PKC?²II and nonphosphorylatable mutant of PKC?²II, PKC?²IIS660A, blocked mTORC1 activity due to lack of PRAS40 phosphorylation, resulting in significant inhibition of HG-induced MC protein synthesis and hypertrophy. Also, PKC?²IIS660A 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 PKC?²II 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 sh Rictor- or shSin1-mediated inhibition of HG-induced MC hypertrophy. Furthermore, CA PKC?²II reversed the shRictor- or shSin1 induced inhibition of HG-stimulated Akt Ser-473 phosphorylation and MC hypertrophy. Finally, we show increased phosphorylation of PKC?²II Ser660, PRAS40 and Akt Ser-473 in association with activation of mTORC1 in renal cortices of OVE26 mice with type 1 diabetes. These results provided the first evidence that HG-induced activation of mTORC2 phosphorylates and activates PKC?²II to increase the phosphorylation of Akt at Ser-473 to finally activate mTORC1 to induce MC hypertrophy. Thus, we uncovered a specific role of mTORC2 for Akt/mTORC1 activation via PKC?²II Ser-660 phosphorylation.

Biography :

Email: [email protected]

Google Scholar citation report
Citations: 708

Journal of Nephrology & Therapeutics received 708 citations as per Google Scholar report

Journal of Nephrology & Therapeutics peer review process verified at publons

Indexed In

 
arrow_upward arrow_upward