@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. 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. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
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",
}