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XPLN is a novel regulator of mTORC2
Author(s) -
Khanidhi,
Fang Yimin,
Yoon MeeSup,
Chen Jie
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.831.2
Subject(s) - mtorc2 , protein kinase b , pi3k/akt/mtor pathway , microbiology and biotechnology , phosphorylation , regulator , guanine nucleotide exchange factor , biology , rhoa , gene knockdown , signal transduction , chemistry , mtorc1 , biochemistry , apoptosis , gene
mTORC2 (mammalian or mechanistic target of rapamycin complex 2) signaling controls a wide range of cellular and developmental processes, but the regulation of mTORC2 is incompletely understood. Here we report the identification of a novel regulator of mTORC2. In a yeast two‐hybrid screen using the C‐terminal 1188 amino acids of mTOR as bait, we identified XPLN (eXchange factor found in platelets and leukemic and neuronal tissues), a GEF (Guanine Exchange Factor) for RhoA and RhoB, as a positive hit. The physical interaction between XPLN and full‐length mTOR was validated by pulldown assays, and found to be dependent on rictor but not raptor suggesting that XPLN specifically interacts with mTORC2. Recombinant XPLN inhibited mTORC2 kinase activity toward Akt in vitro, and overexpression of XPLN suppressed Akt phosphorylation in both HEK293 cells and C2C12 myoblasts. Conversely, knockdown of XPLN increased AKT phosphorylation in those cells. Furthermore, we found that XPLN negatively regulated cell survival and myoblast differentiation through Akt. Surprisingly, these functions of XPLN were independent of its GEF activity. Taken together, our results reveal XPLN as a novel regulator of mTORC2 signaling to Akt in the regulation of cell survival and differentiation. This work was supported by NIH grants to JC (AR048914 & GM089771).