Mammalian EAK-7 activates alternative mTOR signaling to regulate cell proliferation and migration

Science Advances
Joe Truong NguyenPaul H Krebsbach

Abstract

Nematode EAK-7 (enhancer-of-akt-1-7) regulates dauer formation and controls life span; however, the function of the human ortholog mammalian EAK-7 (mEAK-7) is unknown. We report that mEAK-7 activates an alternative mechanistic/mammalian target of rapamycin (mTOR) signaling pathway in human cells, in which mEAK-7 interacts with mTOR at the lysosome to facilitate S6K2 activation and 4E-BP1 repression. Despite interacting with mTOR and mammalian lethal with SEC13 protein 8 (mLST8), mEAK-7 does not interact with other mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2) components; however, it is essential for mTOR signaling at the lysosome. This phenomenon is distinguished by S6 and 4E-BP1 activity in response to nutrient stimulation. Conventional S6K1 phosphorylation is uncoupled from S6 phosphorylation in response to mEAK-7 knockdown. mEAK-7 recruits mTOR to the lysosome, a crucial compartment for mTOR activation. Loss of mEAK-7 results in a marked decrease in lysosomal localization of mTOR, whereas overexpression of mEAK-7 results in enhanced lysosomal localization of mTOR. Deletion of the carboxyl terminus of mEAK-7 significantly decreases mTOR interaction. mEAK-7 knockdown decreases cell proliferation and migration, whereas ove...Continue Reading

References

Sep 22, 1999·Oncogene·K K Lee-FrumanJ Blenis
Aug 31, 2000·Journal of Molecular Biology·C NotredameJ Heringa
Jun 25, 2002·Genes & Development·Diane C FingarJohn Blenis
Sep 28, 2007·Traffic·Bernd SchröderAndrej Hasilik
May 10, 2008·The Biochemical Journal·Jingxiang Huang, Brendan D Manning
May 24, 2008·Science·Yasemin SancakDavid M Sabatini
Apr 3, 2009·Nature Reviews. Molecular Cell Biology·Xiaoju Max Ma, John Blenis
Mar 24, 2011·Cancer Research·Savitha Sridharan, Alakananda Basu
Dec 21, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Kyeongjin KimSung Hee Um
Feb 2, 2012·International Journal of Breast Cancer·Rachel E EllsworthCraig D Shriver
Mar 14, 2012·PloS One·Tamara R CastañedaMatthias H Tschöp
Apr 24, 2013·Nature Reviews. Molecular Cell Biology·Carmine SettembreAndrea Ballabio
Jul 31, 2013·Frontiers in Oncology·Olivier E Pardo, Michael J Seckl
Jan 5, 2014·The Journal of Cell Biology·Charles Betz, Michael N Hall
Feb 22, 2014·Nature Reviews. Molecular Cell Biology·Mitsugu Shimobayashi, Michael N Hall
Nov 2, 2014·Nucleic Acids Research·Kristian A GrayElspeth A Bruford
Mar 12, 2017·Cell·Robert A Saxton, David M Sabatini

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Citations

Feb 8, 2019·Future Oncology·Nurettin İlter Sever, Sevilay Cengiz Şahin
Jun 28, 2019·Frontiers in Genetics·Triin KikasMaris Laan
Sep 25, 2019·The Journal of Biological Chemistry·Shuling ZhangBeverly A Mock
Aug 9, 2020·Genes·Chun-Seok ChoJun Hee Lee
Jul 2, 2020·Genes·Yandong Lai, Yu Jiang
Jul 10, 2019·IScience·Joe Truong NguyenPaul H Krebsbach
Dec 29, 2020·Heliyon·Daniela Baccelli MendonçaPaul H Krebsbach
Feb 19, 2021·Physiological Reviews·Angelia SzwedEstela Jacinto
Aug 21, 2020·Molecular Aspects of Medicine·Juho VuononvirtaThanushiyan Poobalasingam
Mar 12, 2021·Cell Cycle·Zhengfu HeChangxian Shen

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Methods Mentioned

BETA
GTPase
Confocal microscopy
coimmunoprecipitation assay
immunoprecipitation
coimmunoprecipitation
flow cytometry
transfection

Software Mentioned

RTCA
Imaris

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