TORC-Specific Phosphorylation of Mammalian Target of Rapamycin (mTOR): Phospho-Ser2481 Is a Marker for Intact mTOR Signaling Complex 2
- 1 March 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 69 (5), 1821-1827
- https://doi.org/10.1158/0008-5472.can-08-3014
Abstract
The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic component of two evolutionarily conserved signaling complexes. mTOR signaling complex 1 (mTORC1) is a key regulator of growth factor and nutrient signaling. S6 kinase is the best-characterized downstream effector of mTORC1. mTOR signaling complex 2 (mTORC2) has a role in regulating the actin cytoskeleton and activating Akt through S473 phosphorylation. Herein, we show that mTOR is phosphorylated differentially when associated with mTORC1 and mTORC2 and that intact complexes are required for these mTORC-specific mTOR phosphorylations. Specifically, we find that mTORC1 contains mTOR phosphorylated predominantly on S2448, whereas mTORC2 contains mTOR phosphorylated predominantly on S2481. Using S2481 phosphorylation as a marker for mTORC2 sensitivity to rapamycin, we find that mTORC2 formation is in fact rapamycin sensitive in several cancer cell lines in which it had been previously reported that mTORC2 assembly and function were rapamycin insensitive. Thus, phospho-S2481 on mTOR serves as a biomarker for intact mTORC2 and its sensitivity to rapamycin. [Cancer Res 2009;69(5):1821–7]Keywords
Other Versions
This publication has 28 references indexed in Scilit:
- PKBα/Akt1 Acts Downstream of DNA-PK in the DNA Double-Strand Break Response and Promotes SurvivalMolecular Cell, 2008
- Identification of Protor as a novel Rictor-binding component of mTOR complex-2Biochemical Journal, 2007
- The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteinsThe Journal of cell biology, 2004
- Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the CytoskeletonCurrent Biology, 2004
- Thr2446 Is a Novel Mammalian Target of Rapamycin (mTOR) Phosphorylation Site Regulated by Nutrient StatusOnline Journal of Public Health Informatics, 2004
- GβL, a Positive Regulator of the Rapamycin-Sensitive Pathway Required for the Nutrient-Sensitive Interaction between Raptor and mTORMolecular Cell, 2003
- Raptor, a Binding Partner of Target of Rapamycin (TOR), Mediates TOR ActionCell, 2002
- mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth MachineryCell, 2002
- A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells.2000
- FKBP12-Rapamycin-associated Protein (FRAP) Autophosphorylates at Serine 2481 under Translationally Repressive ConditionsJournal of Biological Chemistry, 2000