MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling
Wei Wang, … , David D. Moore, Feng Yang
Wei Wang, … , David D. Moore, Feng Yang
Published January 28, 2019
Citation Information: J Clin Invest. 2019;129(3):1015-1029. https://doi.org/10.1172/JCI97712.
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Research Article Cell biology Oncology

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

Abstract

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.

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

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Figure 2

MAPK4 activates AKT.

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MAPK4 activates AKT. (A) Western blots on MAPK4 expression in various hu...
(A) Western blots on MAPK4 expression in various human cancer cell lines and PNT1A, an immortalized human prostate epithelial cell line. (B) Two distinct shRNAs targeting MAPK4 (G2 and G4 as described in Methods) were used to knock down MAPK4 expression in H157, H1299, HCT116, and VCaP cells. Western blots were used to detect AKT phosphorylation and activation (phosphorylation of GSK3β). (C) MAPK4 was overexpressed in PC3 and PNT1A cells. Western blots were used to detect AKT phosphorylation and activation. (D) CRISPR/Cas9 technology was used to knockout MAPK4 in H157 cells (clones 2, 4, 6) and HCT116 cells (clones 4 and 8). Western blots were used to compare AKT phosphorylation and activation among these cells. (E) MAPK4 was ectopically expressed in the H157 MAPK4-KO cells (clone 2) and HCT116 MAPK4-KO cells (clone 4). Both constitutive and Dox-induced expression systems were used to express MAPK4 in the H157 MAPK4-KO cells. Western blots were used to detect AKT phosphorylation and activation. Ctrl: control; NT: nontargeting control; iMAPK4: Dox-inducible overexpression of MAPK4. Data are representative of at least 3 independent experiments.