title: Regulation of mTORC1 by lysosomal calcium and calmodulin.
abstract: Blockade of lysosomal calcium release due to lysosomal lipid accumulation has been shown to inhibit mTORC1 signaling. However, the mechanism by which lysosomal calcium regulates mTORC1 has remained undefined. Herein we report that proper lysosomal calcium release through the calcium channel TRPML1 is required for mTORC1 activation. TRPML1 depletion inhibits mTORC1 activity, while overexpression or pharmacologic activation of TRPML1 has the opposite effect. Lysosomal calcium activates mTORC1 by inducing association of calmodulin (CaM) with mTOR. Blocking the interaction between mTOR and CaM by antagonists of CaM significantly inhibits mTORC1 activity. Moreover, CaM is capable of stimulating the kinase activity of mTORC1 in a calcium-dependent mannerin vitro. These results reveal that mTOR is a new type of CaM-dependent kinase, and TRPML1, lysosomal calcium and CaM play essential regulatory roles in the mTORC1 signaling pathway.
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.|The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, United States.
authors: Ruo-Jing
authors: RJ
authors: Li
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.|The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, United States.|Eli Lilly and Company, Indianapolis, United States.
authors: Jing
authors: J
authors: Xu
authors: The Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States.
authors: Chenglai
authors: 0000-0003-4300-9948
authors: C
authors: Fu
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, United States.
authors: Jing
authors: J
authors: Zhang
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, United States.
authors: Yujun George
authors: YG
authors: Zheng
authors: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States.
authors: Hao
authors: H
authors: Jia
authors: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States.|The SJ Yan and HJ Mao Laboratory of Chemical Biology, Johns Hopkins University School of Medicine, Baltimore, United States.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, United States.
authors: Jun O
authors: 0000-0003-3842-9841
authors: JO
authors: Liu
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D002147:Calmodulin; C416674:MCOLN1 protein, human; D046912:Multiprotein Complexes; D050051:Transient Receptor Potential Channels; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D002118:Calcium
keywords: biochemistry; calcium; calmodulin; human; mTOR