Content area
Full Text
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.
Introduction
The AKT/mTOR signaling pathway is essential for regulating cell survival, proliferation, and metabolism. In the canonical pathway for AKT activation, PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3), which binds to the pleckstrin homology (PH) domain of AKT, thereby recruiting AKT to the plasma membrane for activation (1-3). Phosphorylation of AKT at Thr308 (T308) of the activation loop by PDK1 (4) and phosphorylation of Ser473 (S473) in the hydrophobic loop are required for full AKT activation. mTOR exists in 2 distinct complexes, mTORCl and mTORC2, which act coordinately with AKT. AKT activates mTORCl, which is an essential hub integrating extracellular stimuli and nutrient signals to regulate cell growth and metabolism (5). In contrast, mTORC2 is a major AKT S473 kinase (6). Precise control of PI3K/AKT/mTOR signaling is crucial for tissue homeostasis, and its aberrant activation leads to a number of pathological outcomes, including cancers. The PI3K/AKT/mTOR pathway has emerged as a major therapeutic target in cancer (7, 8).
The 13 human MAP kinases include the extensively studied ERK1/2 (MAPK3/1), JNK1/2/3 (MAPK8/9/10), and P38a/ß/y/8...