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

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 sig...

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Bibliographic Details
Published in:iScience 2019-07, Vol.17, p.190-207
Main Authors: Nguyen, Joe Truong, Haidar, Fatima Sarah, Fox, Alexandra Lucienne, Ray, Connor, Mendonça, Daniela Baccelli, Kim, Jin Koo, Krebsbach, Paul H.
Format: Article
Language:English
Subjects:
Biological Sciences
Cancer
Cell Biology
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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. [Display omitted] •mEAK-7 forms an alternative mTOR complex with DNA-PK in human cancer•mEAK-7 is upregulated in the metastasized lymph nodes of patients with NSCLC•DNA-PK is essential for mEAK-7-mTOR-S6K2 signaling in human cancer•mEAK-7 is required for cancer cell clonogenicity and spheroid formation Biological Sciences; Cell Biology; Cancer
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2019.06.029