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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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 5

The molecular basis for MAPK4 binding to AKT, part 1.

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The molecular basis for MAPK4 binding to AKT, part 1. (A) The domain arc...
(A) The domain architecture of human MAPK4. MAPK4 contains an N-terminal kinase domain (aa20 to aa312), a conserved C34 (aa313 to aa462) motif shared between MAPK4 (Erk4) and MAPK6 (Erk3), and a C-terminal tail. Asterisk indicates phosphorylation site. (B) HEK293T cells were transfected with FLAG-tagged AKT1 and HA-tagged WT or C-terminally truncated MAPK4 including N462, N312, and N185. Immunoprecipitation was performed using anti-FLAG M2 affinity gel followed by Western blots using anti-HA antibody. The kinase domain of MAPK4 binds to AKT1 and the aa186–aa312 fragment is essential for this interaction. (C) His-tagged AKT1 along with FLAG-tagged MAPK4 and MAPK4S186A mutant were reconstructed into the DLD1 AKT1/2-KO cells that lack all 3 isoforms of AKT. Immunoprecipitation was performed using anti-FLAG M2 affinity gel followed by Western blots for phosphorylation of AKT and total AKT. WCL: whole-cell lysate. (D) HA-tagged AKT2 and AKT3 were reconstructed into the DLD1 AKT1/2-KO cells along FLAG-tagged MAPK4 or MAPK4S186A mutant. Western blots using Phospho-AKT T308 antibody were used to detect the phosphorylation of AKT2 at T309 and AKT3 at T305, respectively. (E) FLAG-tagged MAPK4 and MAPK4S186A mutant were transduced into the H157 MAPK4-KO cells. Western blots were used to determine AKT phosphorylation. Ctrl: control. Data are representative of at least 3 independent experiments.