The mammalian target of rapamycin (mTOR) assembles a signaling network that is a master regulator of cell growth, proliferation, differentiation, and metabolism. The mTOR network senses the availability of nutrients (amino acids, in particular), and integrates other types of environmental cues, including growth factors, cellular energy levels, and various types of stress. Rapamycin, an exquisitely specific inhibitor for mTOR, is a bacterial macrolide that has tremendous clinical values, such as an immunosuppressant to prevent graft rejection after transplantation, an anti-restenosis agent used in angioplasty stenting, and an anti-cancer drug. Our lab has made seminal contributions to the field uncovering multiple mechanisms of mTOR signaling, most notably a direct link between the lipid second messenger phosphatidic acid and mTOR complex 1 (mTORC1).
M. Vilella-Bach, P. Nuzzi, Y. Fang and J. Chen (1999) The FKBP12-Rapamycin-binding Domain Is Required for FKBP12-Rapamycin-associated Protein Kinase Activity and G1 Progression, J. Biol. Chem. 274, 4266-72. Link to article
E. Kim and J. Chen (2000) Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation, Proc. Natl. Acad. Sci. USA 97, 14340-5. Link to article
M. Hartman, M. Vilella-Bach, J. Chen and G. Freund (2001) FRAP-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation, Biochem. Biophys. Res. Comm. 280, 776-81.
Y. Fang, M. Viella-Bach, R. Bachmann, A. Flanigan and J. Chen (2001) Phosphatidic acid-mediated mitogenic activation of mTOR signaling, Science 294, 1942-5. Link to article
I.-H. Park, R. Bachmann, H. Shirazi and J. Chen (2002) Regulation of S6 kinase 2 by the mammalian target of rapamycin, J. Biol. Chem. 277, 31423-9.
J. Chen and Y. Fang (2002) A novel pathway regulating the mammalian target of rapamycin signaling, Biochem. Pharm. 64, 1071-7.
Y. Fang, I.-H. Park, A. Wu, G. Du, P. Huang, M.A. Frohman, S.J. Walker, H.A. Brown and J. Chen (2003) PLD1 regulates mTOR signaling and mediates Cdc42 activation of S6K1, Current Biology 13, 2037-44. Link to article
J. Chen (2004) Novel regulatory mechanisms of mTOR signaling, Curr. Top. Microbiol. and Immunol. 279, 245-57.
Y. Xu, Y. Fang, J. Chen and G. Prestwich (2004) Activation of mTOR signaling by novel fluoromethylene phosphonate analogues of phosphatidic acid, Bioorganic & Medicinal Chemistry Letters 14, 1461-4.
E. Erbay, J. E. Kim and J. Chen (2005) Amino acid-sensing mTOR signaling, a chapter in Nutrients and Cell Signaling, CRC Press, p353-380
R. A. Bachmann, J.-H. Kim, A.-L. Wu, I.-H. Park and J. Chen (2006) A nuclear transport signal in mammalian target of rapamycin is critical for its cytoplasmic signaling to S6 kinase 1, J. Biol. Chem. 281, 7357-63.
J.-H. Kim, J. E. Kim, H.-Y. Liu, W. Cao and J. Chen (2008) Regulation of IL-6 induced hepatic insulin resistance by mTOR through the STAT3-SOCS3 pathway, J. Biol. Chem. 283, 708-15. Link to article
Y. Sun, Y. Fang, M.-S. Yoon, C. Zhang, M. Roccio, F. J. Zwartkrause, M. Armstrong, H. A. Brown and J. Chen (2008) Phospholipase D1 is an effector of Rheb in the mTOR pathway, Proc. Natl. Acad. Sci. USA 105, 8286-91 (PMC2448829). Link to article
Y. Sun and J. Chen (2008) mTOR signaling: PLD takes center stage, Cell Cycle, 7, 3118-23.
J.-H. Kim, M.-S. Yoon and J. Chen, (2009) Signal transducer and activator of transcription 3 (STAT3) mediates amino acids-induced insulin resistance through Ser727 phosphorylation, J. Biol. Chem., 284, 35425. (PMC2790971).
M.-S. Yoon, G. Du, J. M. Backer, M. A. Frohman, and J. Chen, (2011) Class III PI-3-kinase activates phospholipase D in an amino acid-sensing mTORC1 pathway, J. Cell Biol. 195, 435-47. [Highlighted in JCB News: In this issue; Perspective in Science Signaling 5:pe13, 2012] (PMC3206351). Link to article
N. Khanna, Y. Fang, M.-S. Yoon, and J. Chen, (2013) XPLN is an endogenous inhibitor of mTORC2. Proc. Natl. Acad. Sci. USA, 110, 15979-84. (direct submission) (PMC3791717). Link to article
M.-S. Yoon†, C.L. Rosenberger†, C. Wu, N. Truong, J.V. Sweedler, and J. Chen, (2015) Rapid mitogenic regulation of the mTORC1 inhibitor, DEPTOR, by phosphatidic acid, Mol. Cell, 58, 549-556. (Cover art image) [Recommended as “exceptional” by Faculty-1000] (†co-first authors). Link to article
M.-S. Yoon†, K. Son†, E. Arauz, J. M. Han, S. Kim, and J. Chen, (2016) Leucyl-tRNA synthetase activates Vps34 in amino acid-sensing mTORC1 signaling, Cell Rep 16, 1510-17 (†co-first authors). Link to article