Sphingolipids mediate the signals for all the essential functions of Target Of Rapamycin Complex 2

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.