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

Abstract

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.

• Authors: Joe Truong Nguyen, Fatima Sarah Haidar, Alexandra Lucienne Fox, Connor Ray, Daniela Baccelli Mendonça, Jin Koo Kim, Paul H Krebsbach
• Journal: iScience (iScience) Vol. 17 Pg. 190-207 (Jul 26 2019) ISSN: 2589-0042 [Electronic] United States
• PMID: 31288154 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.