Two TOR Complexes, Only One of which Is Rapamycin Sensitive, Have Distinct Roles in Cell Growth Control

Abstract

The target of rapamycin (TOR) proteins in Saccharomyces cerevisiae, TOR1 and TOR2, redundantly regulate growth in a rapamycin-sensitive manner. TOR2 additionally regulates polarization of the actin cytoskeleton in a rapamycin-insensitive manner. We describe two functionally distinct TOR complexes. TOR Complex 1 (TORC1) contains TOR1 or TOR2, KOG1 (YHR186c), and LST8. TORC2 contains TOR2, AVO1 (YOL078w), AVO2 (YMR068w), AVO3 (YER093c), and LST8. FKBP-rapamycin binds TORC1, and TORC1 disruption mimics rapamycin treatment, suggesting that TORC1 mediates the rapamycin-sensitive, TOR-shared pathway. FKBP-rapamycin fails to bind TORC2, and TORC2 disruption causes an actin defect, suggesting that TORC2 mediates the rapamycin-insensitive, TOR2-unique pathway. Thus, the distinct TOR complexes account for the diversity, specificity, and selective rapamycin inhibition of TOR signaling. TORC1 and possibly TORC2 are conserved from yeast to man.

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

“…In contrast to raptor, rictor was recently identified in both yeast and mammals as a novel mTOR-interacting protein (Loewith et al, 2002). Unlike its mTOR-raptor sibling, the mTOR-rictor complex does not bind to FKBP12-rapamycin and is insensitive to rapamycin.…”

“…Moreover, rapamycin does not inhibit all mTOR functions, because mTOR exists in cells at least two distinct multiprotein complexes and only one of which binds to FKBP12-rapamycin (Loewith et al, 2002). The rapamycin-sensitive complex is defined by the interaction of mTOR with the accessory protein raptor (regulatory-associated protein of mTOR), and the rapamycin-insensitive complex interacts with rictor (rapamycin-insensitive companion of mTOR) (Guertin and Sabatini, 2005).…”

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

“…Arrows and bars represent positive and negative interactions, respectively. Dashed lines represent putative or indirect interactions http://doc.rero.ch TOR multiprotein complexes exist: TOR complex 1 (TORC1) and TOR complex 2 (TORC2) (Zheng et al 1995;Loewith et al 2002); however, only TORC1 is specifically inhibited by rapamycin (Fig. 4).…”

“…Both Tor1 as well as Tor2 can be found in the multiprotein TORC1 together with Lst8, Kog1 and Tco89. A separate pool of Tor2 also associates with Lst8, Avo1, Avo2, Avo3, Bit61 and Bit2 to form TORC2 (Loewith et al 2002;Chen and Kaiser 2003;Wedaman et al 2003;Reinke et al 2004;Araki et al 2005;Fadri et al 2005). The precise function of these TORinteracting proteins is not known yet.…”

“…The TOR complexes are likely dimeric built on a TOR-TOR dimer . Only TORC1 can bind FKBP12-rapamycin while in TORC2, the Tor2 FKBP12-rapamycin binding domain is probably not exposed for binding (Loewith et al 2002), explaining why only TORC1 signalling is sensitive to rapamycin treatment. Interestingly, the constitution of TORC1 appears to be unaffected by rapamycin, implying that rapamycin does not inhibit TORC1 signalling by interfering with TORC1 stability (Loewith et al 2002).…”