MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling

• DOI: 10.1172/jci97712
• Publication Date: 2019-01-27T23:00:54Z
• Authors: Wei Wang; Tao Shen; Bingning Dong; Chad J. Creighton; Yanling Meng; Wolong Zhou; Qing Shi; Hao Zhou; Yinjie Zhang; David D. Moore; Feng Yang
• Keywords: Urologic Diseases; Enzymologic; Male; 0301 basic medicine; Biomedical and clinical sciences; Oncology and Carcinogenesis; Nude; Immunology; Mice, Nude; Mice, SCID; SCID; Medical and Health Sciences; Gene Expression Regulation, Enzymologic; Experimental; Mice; 03 medical and health sciences; Neoplasms; Genetics; 2.1 Biological and endogenous factors; Animals; Humans; Aetiology; Cancer; Neoplastic; 0303 health sciences; Biomedical and Clinical Sciences; TOR Serine-Threonine Kinases; Health sciences; Cell Biology; Oncogenes; Neoplasms, Experimental; Biological Sciences; HCT116 Cells; 3. Good health; Enzyme Activation; Gene Expression Regulation, Neoplastic; Biological sciences; Gene Expression Regulation; Oncology; PC-3 Cells; Proto-Oncogene Proteins c-akt; RNA Helicases; Biotechnology; Signal Transduction

MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.