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
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
