ArticleProceedings of the National Academy of Sciences of the United States of America2013
XPLN is an endogenous inhibitor of mTORC2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 44 citations in OpenAlex.
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- ARHGEF3 coordinates adipocyte hypertrophy and differentiation through dual YAP-RhoA and PPARγ activation.Journal of advanced research · 2026Article
- The Rho GTPase regulator ARHGEF3 orchestrates hair placode budding by coordinating cell fate and P-cadherin patterning in mice.PLoS biology · 2026Article
- Regulation of Rho guanine nucleotide exchange factor 3 by phosphorylation in the PH domain.iScience · 2025Article
- ARHGEF3 Regulates Hair Follicle Morphogenesis.bioRxiv : the preprint server for biology · 2024Article
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
- RhoA/ROCK signalling activated by ARHGEF3 promotes muscle weakness via autophagy in dystrophic mdx mice.Journal of cachexia, sarcopenia and muscle · 2023Article
- Integration of Transcriptomics and Non-Targeted Metabolomics Reveals the Underlying Mechanism of Skeletal Muscle Development in Duck during Embryonic Stage.International journal of molecular sciences · 2023Article
- ARHGEF3 regulates the stability of ACLY to promote the proliferation of lung cancer.Cell death & disease · 2022Article
- A Human and Rhesus Macaque Interferon-Stimulated Gene Screen Shows That Over-Expression ofViruses · 2022Article
- The central moTOR of metabolism.Developmental cell · 2022Review
- Article
- Redefining the specificity of phosphoinositide-binding by human PH domain-containing proteins.Nature communications · 2021Article
- Article
- Role of ARHGEF3 as a GEF and mTORC2 Regulator.Frontiers in cell and developmental biology · 2021Review
- Vav2 pharmaco-mimetic mice reveal the therapeutic value and caveats of the catalytic inactivation of a Rho exchange factor.Oncogene · 2020Article
- Nanotechnology-Based Targeting of mTOR Signaling in Cancer.International journal of nanomedicine · 2020Review
- Homer1 mediates CaSR-dependent activation of mTOR complex 2 and initiates a novel pathway for AKT-dependent β-catenin stabilization in osteoblasts.The Journal of biological chemistry · 2019Article
- Targeting mTOR for cancer therapy.Journal of hematology & oncology · 2019Review
- Adrenoceptor regulation of the mechanistic target of rapamycin in muscle and adipose tissue.British journal of pharmacology · 2019Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Mammalian target of rapamycin complex 2 (mTORC2) controls a wide range of cellular and developmental processes, but its regulation remains incompletely understood. Through a yeast two-hybrid screen, we have identified XPLN (exchange factor found in platelets, leukemic, and neuronal tissues), a guanine nucleotide exchange factor (GEF) for Rho GTPases, as an interacting partner of mTOR. In mammalian cells, XPLN interacts with mTORC2 but not with mTORC1, and this interaction is dependent on rictor. Knockdown of XPLN enhances phosphorylation of the Ser/Thr kinase Akt, a target of mTORC2, whereas overexpression of XPLN suppresses it, suggesting that XPLN inhibits mTORC2 signaling to Akt. Consistent with Akt promoting cell survival and XPLN playing a negative role in this process, XPLN knockdown protects cells from starvation-induced apoptosis. Importantly, this effect of XPLN depletion is abolished by inhibition of Akt or mTOR kinase activity, as well as by rictor knockdown. In vitro, purified XPLN inhibits mTORC2 kinase activity toward Akt without affecting mTORC1 activity. Interestingly, the GEF activity of XPLN is dispensable for its regulation of mTORC2 and Akt in cells and in vitro, whereas an N-terminal 125-amino-acid fragment of XPLN is both necessary and sufficient for the inhibition of mTORC2. Finally, as a muscle-enriched protein, XPLN negatively regulates myoblast differentiation by suppressing mTORC2 and Akt, and this function is through the XPLN N terminus and independent of GEF activity. Our study identifies XPLN as an endogenous inhibitor of mTORC2 and delineates a noncanonical mechanism of XPLN action.
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