Helliwell, Stephen, Abraham, Yann, Movva, Rao, Filipuzzi, Ireos, Stahl, Michael, Rispal, Delphine, Eltschinger, Vaga, Bodenmiller, Bernd, Aebersold, Ruedi, Loewith, Robbie and Vaga, Stefania (2015) Sphingolipids mediate the signals for all the essential functions of Target Of Rapamycin Complex 2. Journal of Biological Chemistry, tba (o.

Abstract

Target Of Rapamycin (TOR) signaling is widely conserved amongst Eukarya serving to maintain homeostasis at both the cellular and organism level. TOR is a Ser/Thr kinase that operates in two distinct, multiprotein complexes known as TOR Complex 1 (TORC1) and TORC2. Rapamycin specifically and potently (at least in yeast), inhibits TORC1; and, this macrolide has thus greatly facilitated characterization of TORC1 signaling. Lacking a rapamycin-like equivalent tool for TORC2, dissection of the pathways in which this kinase complex operates has lagged relative to TORC1. To address this, we have utilized a novel, yeast-permeant, small molecule TOR inhibitor to identify the TORC2-dependent phosphoproteome. We discovered that many of the distal effectors downstream of TORC2, including actin polarization, calcineurin and G2/M cell cycle progression are indirectly regulated via TORC2’s influence on sphingolipid production. This observation supports the concept that beyond their structural functions, sphingolipids play fundamental roles in transducing intracellular signals.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/10314