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 March 1, 2019; First published January 28, 2019
Citation Information: J Clin Invest. 2019;129(3):1015-1029. https://doi.org/10.1172/JCI97712.
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Categories: 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 1

Overexpression of MAPK4 in a subset of human cancers is associated with decreased overall survival and increased AKT activity.

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Overexpression of MAPK4 in a subset of human cancers is associated with ...
(A) Upper panel, MAPK4 mRNA expression across 8887 tumors of various histological subtypes from The Cancer Genome Atlas (TCGA). Lower panel, Kaplan-Meier plot of overall survival in patients across all TCGA data sets, as stratified by high MAPK4 expression. P values by log-rank test and by stratified log-rank test (correcting for tumor type), as indicated. (B) Kaplan-Meier plot of overall survival in patients within specific cancer types, as stratified by high MAPK4 expression. BLCA, bladder cancer; LGG, low-grade glioma; LUAD, lung adenocarcinoma; THCA, thyroid carcinoma. P values by log-rank test. (C) Heatmaps showing the correlation of MAPK4 expression with expression of specific proteins profiled in TCGA pan-cancer datasets by Pearson’s coefficient. Significance of correlation: P < 1 × 10–17 for each protein feature.