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

  • Sci Adv. 2018 May 9;4(5):eaao5838. doi: 10.1126/sciadv.aao5838.
Joe Truong Nguyen  1  2 ,  Connor Ray  1  2 ,  Alexandra Lucienne Fox  1  2 ,  Daniela Baccelli Mendonça  1  2 ,  Jin Koo Kim  1  2  3 ,  Paul H Krebsbach  1  2  3
Affiliations
  • 1. Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48105, USA.
  • 2. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA.
  • 3. Section of Periodontics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
PMID: 29750193 DOI: 10.1126/sciadv.aao5838
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 overexpression of mEAK-7 enhances these cellular effects. Constitutively activated S6K rescues mTOR signaling in mEAK-7-knocked down cells. Thus, mEAK-7 activates an alternative mTOR signaling pathway through S6K2 and 4E-BP1 to regulate cell proliferation and migration.