Sphingosine-1-phosphate induced mTOR-activation is mediated by the E3-ubiquitin ligase PAM |
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| Authors: | Christian Maeurer Sabrina Holland Sandra Pierre Wiebke Potstada Klaus Scholich |
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| Institution: | 1. Department of Surgery, Georgetown University Hospital, Washington, DC;2. MedStar-Georgetown Surgical Outcomes Research Center, Washington, DC;3. MedStar Health Research Institute, Washington, DC;4. Lombardi Comprehensive Cancer Center, Washington, DC;1. Department of Surgery, Borgess Medical Center, Kalamazoo, Michigan;2. Department of Surgery and Center for Healthcare Outcomes and Policy, University of Michigan, Ann Arbor, Michigan;1. Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju 361-763, South Korea;2. Department of Pathology, Bundang Hospital, Seoul National University College of Medicine, 103 Daehakro, Jongno-gu, Seoul 110-799, South Korea;3. Department of Pathology, College of Medicine, Chungbuk National University, Cheongju 361-763, South Korea;4. Department of Natural Sciences, School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-701, South Korea;5. Division of Bioscience and Bioinformatics, Myongji University, Yoingin-si 449-728, South Korea;6. Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, Singapore 117599, Singapore |
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| Abstract: | The signaling pathways that are regulated by sphingosine-1-phosphate (S1P) and mammalian target of rapamycin (mTOR) modulate cell growth, mitogenesis and apoptosis in various cell types and are of major interest for the development of new cancer therapeutics. Previous reports show that S1P can cross-activate the mTOR pathway although the mechanisms that connect both pathways are still unknown. We found that S1P-treatment activates mTOR in several cancer cell lines and primary cells. The activation was independent of ERK, Akt and PI3-kinase, but instead was mediated by the E3 ubiquitin ligase Protein Associated with Myc (PAM). Increased intracellular PAM concentrations facilitated S1P- and insulin-induced mTOR activation as well as p70S6K and 4EBP1 phosphorylation while genetic deletion of PAM decreased S1P- and insulin-induced mTOR activation. PAM activated by facilitating the GDP/GTP-exchange of Rheb which is an activator of mTOR. In conclusion we show that PAM is a novel regulator of the mTOR pathway and that PAM may directly activate Rheb as a guanosine exchange factor (GEF). |
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