mEAK-7 Forms an Alternative mTOR Complex with DNA-PKcs in Human Cancer

Joe Truong Nguyen; Fatima Sarah Haidar; Alexandra Lucienne Fox; Connor Ray; Daniela Baccelli Mendonça; Jin Koo Kim; Paul H. Krebsbach

iScience (Jul 2019)

mEAK-7 Forms an Alternative mTOR Complex with DNA-PKcs in Human Cancer

Joe Truong Nguyen,
Fatima Sarah Haidar,
Alexandra Lucienne Fox,
Connor Ray,
Daniela Baccelli Mendonça,
Jin Koo Kim,
Paul H. Krebsbach

Affiliations

Joe Truong Nguyen: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA
Fatima Sarah Haidar: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA
Alexandra Lucienne Fox: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA
Connor Ray: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA
Daniela Baccelli Mendonça: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109, USA
Jin Koo Kim: Section of Periodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
Paul H. Krebsbach: Section of Periodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author

Journal volume & issue: Vol. 17
pp. 190 – 207

Abstract

Read online

Summary: MTOR associated protein, eak-7 homolog (mEAK-7), activates mechanistic target of rapamycin (mTOR) signaling in human cells through an alternative mTOR complex to regulate S6K2 and 4E-BP1. However, the role of mEAK-7 in human cancer has not yet been identified. We demonstrate that mEAK-7 and mTOR signaling are strongly elevated in tumor and metastatic lymph nodes of patients with non-small-cell lung carcinoma compared with those of patients with normal lung or lymph tissue. Cancer stem cells, CD44+/CD90+ cells, yield elevated mEAK-7 and activated mTOR signaling. mEAK-7 is required for clonogenic potential and spheroid formation. mEAK-7 associates with DNA-dependent protein kinase catalytic subunit isoform 1 (DNA-PKcs), and this interaction is increased in response to X-ray irradiation to regulate S6K2 signaling. DNA-PKcs pharmacologic inhibition or genetic knockout reduced S6K2, mEAK-7, and mTOR binding with DNA-PKcs, resulting in loss of S6K2 activity and mTOR signaling. Therefore, mEAK-7 forms an alternative mTOR complex with DNA-PKcs to regulate S6K2 in human cancer cells. : Biological Sciences; Cell Biology; Cancer Subject Areas: Biological Sciences, Cell Biology, Cancer

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

About the journal