Journal
CELL
Volume 171, Issue 7, Pages 1545-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.10.037
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Funding
- NIH [R01 CA046595, R01 HL121266, R01 GM051405, P01 CA120964, R01 GM041890, R35 CA197588, R01 CA16359, R01 HL098216, R01 DK098331, R01 GM62891, R01 GM122610, R01 AG54215, R01 GM114160]
- Stand Up to Cancer grant [SU2C-AACR-DT0509]
- Ellison Medical Foundation
- Welch Foundation [I-1800]
- LAM Foundation [LAM00100F01-14]
- Tuberous Sclerosis Alliance [TSA-01-14]
- National Research Foundation of Korea [2012R1A6A3-A03039825]
- Department of Defense Breast Cancer Research Program [W81XWH-13-1-0251]
- Kwanjeong Educational Foundation
- American Diabetes Association [1-17-PDF-076]
- American Federation for Aging Research
- Petra
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mTORC1is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. Genome-wide transcriptome analysis reveals that lipid biosynthetic enzymes are among the downstream targets of mTORC1-SRPK2 signaling. Mechanistically, SRPK2 promotes SR protein binding to U1-70K to induce splicing of lipogenic pre-mRNAs. Inhibition of this signaling pathway leads to intron retention of lipogenic genes, which triggers nonsense-mediated mRNA decay. Genetic or pharmacological inhibition of SRPK2 blunts de novo lipid synthesis, thereby suppressing cell growth. These results thus reveal a novel role of mTORC1-SRPK2 signaling in post-transcriptional regulation of lipid metabolism and demonstrate that SRPK2 is a potential therapeutic target for mTORC1-driven metabolic disorders.
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