Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis

Xie，Jianling1; Shen，Kaikai2,3; Jones，Ashley T.4; Yang，Jian4; Tee，Andrew R.4; Shen，Ming Hong4; Yu，Mengyuan3; Irani，Swati5,6; Wong，Derick1; Merrett，James E.1,7; Lenchine，Roman V.1,7; De Poi，Stuart1,7; Jensen，Kirk B.1,7; Trim，Paul J.8; Snel，Marten F.8; Kamei，Makoto8; Martin，Sally Kim6,9; Fitter，Stephen6,9; Tian，Shuye1,10; Wang，Xuemin1,8; Butler，Lisa M.5,6; Zannettino，Andrew C.W.6,9; Proud，Christopher G.1,8

2020

10.1007/s00018-020-03491-1

CELLULAR AND MOLECULAR LIFE SCIENCES   影响因子和分区

1420-682X

1420-9071

eIF4E plays key roles in protein synthesis and tumorigenesis. It is phosphorylated by the kinases MNK1 and MNK2. Binding of MNKs to eIF4G enhances their ability to phosphorylate eIF4E. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G. These effects provide a novel mechanism by which mTORC1 signaling impairs the function of MNK2 and thereby decreases eIF4E phosphorylation. MNK2[S74A] knock-in cells show enhanced phosphorylation of eIF4E and S6K1 (i.e., increased mTORC1 signaling), enlarged cell size, and increased invasive and transformative capacities. MNK2[Ser74] phosphorylation was inversely correlated with disease progression in human prostate tumors. MNK inhibition exerted anti-proliferative effects in prostate cancer cells in vitro. These findings define a novel feedback loop whereby mTORC1 represses MNK2 activity and oncogenic signaling through eIF4E phosphorylation, allowing reciprocal regulation of these two oncogenic pathways.

eIF4E mRNA translation Prostate cancer Protein synthesis Rapamycin

SCI

英语

其他

Science Foundation for Distinguished Young Scholar of Shanghai, China[2017067] ; Xinglin Scholar Talent Program from Shanghai University of Traditional Chinese Medicine, China[A1-U17205010436] ; Movember Foundation/Prostate Cancer Foundation of Australia[MRTA3] ; Cancer Australia[1138766]

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:000564403700001

SPRINGER BASEL AG

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85081745513

Scopus

1.Lifelong Health Theme,South Australian Health and Medical Research Institute,Adelaide,North Terrace,5000,Australia
2.Medical Research Council Toxicology Unit,Leicester,United Kingdom
3.School of Basic Medical Sciences,Shanghai University of Traditional Chinese Medicine,Shanghai,201203,China
4.Division of Cancer and Genetics,Cardiff University,Heath Park,Cardiff,United Kingdom
5.Adelaide Medical School and Freemasons Foundation Centre for Men’s Health,University of Adelaide,Adelaide,Australia
6.Precision Medicine Theme,South Australian Health and Medical Research Institute,Adelaide,Australia
7.Department of Molecular and Cellular Biology,University of Adelaide,Adelaide,Australia
8.Hopwood Centre for Neurobiology,South Australian Health and Medical Research Institute,Adelaide,Australia
9.Myeloma Research Laboratory,Adelaide Medical School,Faculty of Health and Medical Science,University of Adelaide,Adelaide,Australia
10.Department of Biology,Southern University of Science and Technology,Shenzhen,China

Xie，Jianling,Shen，Kaikai,Jones，Ashley T.,et al. Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis[J]. CELLULAR AND MOLECULAR LIFE SCIENCES,2020.

Xie，Jianling.,Shen，Kaikai.,Jones，Ashley T..,Yang，Jian.,Tee，Andrew R..,...&Proud，Christopher G..(2020).Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis.CELLULAR AND MOLECULAR LIFE SCIENCES.

Xie，Jianling,et al."Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis".CELLULAR AND MOLECULAR LIFE SCIENCES (2020).