@article{264643317203471fbcce907992b99490,
title = "Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling",
abstract = "mTORC1 is 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. An mTOR-dependent pathway is a key post-transcriptional regulator of lipogenic enzymes that are involved in tumor growth.",
keywords = "CK1, RNA splicing, RNA stability, S6K1, SR proteins, SRPK2, cancer metabolism, de novo lipid synthesis, mTOR, nonsense-mediated decay",
author = "Gina Lee and Yuxiang Zheng and Sungyun Cho and Cholsoon Jang and Christina England and Dempsey, {Jamie M.} and Yonghao Yu and Xiaolei Liu and Long He and Cavaliere, {Paola M.} and Andre Chavez and Erik Zhang and Meltem Isik and Anthony Couvillon and Dephoure, {Noah E.} and Blackwell, {T. Keith} and Yu, {Jane J.} and Rabinowitz, {Joshua D.} and Cantley, {Lewis C.} and John Blenis",
note = "Funding Information: We thank members of Blenis lab, Dennis Liang Fei, Jared Johnson, Florian Karreth, Jihye Yun, Xu Xu, and Ann-Hwee Lee (Weill Cornell Medicine) for discussions and technical assistance. We also would like to thank Brendan Manning (Harvard School of Public Health), Hong-Wen Tang and Norbert Perrimon (Harvard Medical School), Hanseul Yang (Rockefeller University), and Keqiang Ye (Emory University) for discussions. This work was supported by NIH grants R01 CA046595 , R01 HL121266 , and R01 GM051405 (to J.B.), P01 CA120964 , R01 GM041890 , and R35 CA197588 (to L.C.C.), R01 CA16359 (to J.D.R.), R01 HL098216 and R01 DK098331 (to J.J.Y.), R01 GM62891 , R01 GM122610 , and R01 AG54215 (to T.K.B.), and R01 GM114160 (to Y.Y.); Stand Up to Cancer grant SU2C-AACR-DT0509 (to J.D.R.); the Ellison Medical Foundation (to T.K.B.); and the Welch Foundation ( I-1800 ; to Y.Y.). This work was partially supported by fellowships from the LAM Foundation ( LAM00100F01-14 ), the Tuberous Sclerosis Alliance ( TSA-01-14 ), and the National Research Foundation of Korea ( 2012R1A6A3-A03039825 to G.L.), the Department of Defense Breast Cancer Research Program ( W81XWH-13-1-0251 to Y.Z.), the Kwanjeong Educational Foundation (to S.C.), the American Diabetes Association ( 1-17-PDF-076 to C.J.), and the American Federation for Aging Research (to M.I.). L.C.C. is a founder and member of the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals, a company developing drugs that target metabolism for cancer therapy; he is also a founder and member of the Scientific Advisory Board of Petra Pharmaceuticals and receives research support from Petra. ",
year = "2017",
month = dec,
day = "14",
doi = "10.1016/j.cell.2017.10.037",
language = "English (US)",
volume = "171",
pages = "1545--1558.e18",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "7",
}