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

Wang, Wei; Shen, Tao; Dong, Bingning; Creighton, Chad J.; Meng, Yanyan; Zhou, Wolong; Shi, Qing; Zhou, Hao; Zhang, Yinjie; Moore, David D.; Yang, Feng Chun

doi:10.1172/jci97712

Cited by 69 publications

(124 citation statements)

References 36 publications

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“…In present study, we found that MAPK4 de ciency could decrease the expressions of p-AKT, p-JNK and p-p38 MAPK in ALI model. Similarly, Wang et al demonstrated that MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308, thereby inducing oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth [14]. However, we didn't nd that the possible in uence of MAPK4 de ciency on the expression of p-NF-κB in ALI model, indicating there might be other nuclear regulating pathways.…”

Section: Discussionmentioning

confidence: 55%

“…Menezes-Souza et al found that MAPK3 and MAPK4 recombinant proteins showed better speci city in the immunodiagnosis of human leishmaniasis than soluble parasite antigen [13]. Most recently, Wang et al further reported that MAPK4 overexpression could promote the progression of lung cancer, indicating MAPK4 is a potential target for lung cancer therapy [14]. These ndings indicate that MAPK4 play important roles in the development of various types of diseases.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Mao

Zhou

Chen

et al. 2020

Preprint

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Background: Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. Results: We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4-/- mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 inhibition using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions: Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Mao

Zhou

Chen

et al. 2020

Preprint

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“…In present study, we found that MAPK4 deficiency could decrease the expressions of p-AKT, p-JNK and p-p38 MAPK in ALI model. Similarly, Wang et al demonstrated that MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308, thereby inducing oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth [14]. Therefore, these data might highlight the underlying connection among conventional MAPKs, atypical MAPKs and other signaling pathways.…”

Section: Discussionmentioning

confidence: 88%

“…Interestingly, EI-Aarag et al found that MAPK4 was closely related to the development of lung cancer [13]. Most recently, Wang et al further reported that MAPK4 overexpression could promote the progression of lung cancer, indicating MAPK4 is a potential target for lung cancer therapy [14]. These researches have raised an interesting question that MAPK4 might be, as an important regulator, involved in the development of lung diseases.…”

Section: Introductionmentioning

confidence: 99%

NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

Mao

Zhou

et al. 2020

Preprint

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BackgroundAcute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. MAPK4, a member of atypical MAPK family, has been implicated in the development of cancer. Herein, the current study aimed to investigate the possible role of MAPK4 in the pathology of ALI to identify potential candidates for ALI therapy. MethodsMurine ALI model was established in WT or MAPK4 -/mice and the expressions of MAPK4 were measured. The survival ratio of ALI model mice was observed. Moreover, the changes of pathologic injury and infiltration of inflammatory cells, as well as the related signaling pathways, in lung tissues were analyzed. Furthermore, the possible molecular mechanism of MAPK4 expression in ALI was analyzed by massARRAY and EMSA assay. Finally, the effect of MAPK4 silencing using shRNA interference on the pathology of ALI was identified. the expression of MAPK4 by binding to the core sequence of MAPK4 promoter. Importantly, MAPK4-shRNA treatment could significantly reduce the pathology of lung tissues and prolong survival time of ALI mice. Altogether, our study reveals an unknown role of MAPK4 in the pathology of ALI, indicating that MAPK4 might be a new therapeutic target for clinic therapy against ALI. Materials And MethodsMice MAPK4 deficiency (MAPK4 -/-) mice breeding pair in a C57BL/6 background were purchased from The Jackson Laboratory (027666). Animals were housed under specific pathogen-free conditions at Zunyi Medical University. Cell cultureRaw264.7 cells were purchased from Conservation Genetics CAS Kunming Cell Bank (KCB200603YJ), and were cultured in high glucose DEME containing 10% fetal bovine serum at 37°C in 5% CO 2 . Establishment of ALI ModelWT and MAPK4 -/mice (7 to 9 week-old) were challenged with i.p. injection of 10mg/kg LPS (Escherichia coli 0111:B4; Sigma) dissolved in sterile PBS as shown in our previous study [17]. Then the body weight and lung weight index (lung weight/body weight) was detected at indicated time. Bronchoalveolar LavageImmediately after euthanasia, 1 ml aliquots of PBS were slowly infused in the murine lungs through the tracheostomy and then withdrawn gently. This lavage was repeated three times using the same syringe. The collected lavage fluid was stored in a 10ml tube on ice. The fluid was centrifuged at 1000rpm and 4°C for 10 min, and the cell sediment was washed with PBS. The cell-free supernatant was centrifuged again at 14,000g and 4°C for 10 min, stored at −80°C and used for determination of cytokines content via ELISA. To the pellet, red blood lysis buffer (Solarbio, R1010) were used for 15 min and washed with PBS. Next, the pellet was resuspended for analysis. Lung edema determinationLungs from mice were excised and completely dried in the oven at 60°C 24h for calculation of lung wet/dry ratio.

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“…Human MAPK4 and MAPK6 both contain an N-terminal kinase domain of 73% identity, a C34 region of nearly 50% identity, and a C-terminal extension that is not conserved (1). We recently reported that MAPK4 promotes cancer by functioning as a non-canonical AKT kinase independent of PI3K (19). This raised the question of whether AKT is also a substrate of MAPK6 and whether MAPK6 possesses tumor-promoting activity by activating AKT.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic Activation of AKT by MAPK6

Cai

Wang

Dong

et al. 2020

Preprint

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Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK closely related to MAPK4. We recently reported that MAPK4 can promote cancer by activating the Protein Kinase B (PKB/AKT) pathway of cell growth and survival. Here we report that MAPK6 overexpression also activates AKT to induce oncogenic outcomes, including transforming “normal” human epithelial cells into anchorage-independent growth and enhancing cancer cell growth. Knockdown of MAPK6 inhibited cancer cell growth and xenograft growth, supporting the tumor-promoting activities of endogenous MAPK6. Unlike MAPK4, which binds AKT through its kinase domain and phosphorylates AKT at T308, MAPK6 interacts with AKT through its C34 region and the unique C-terminal tail and phosphorylates AKT at S473 independent of mTORC2, the major AKT S473 kinase. MAPK6 overexpression is associated with decreased overall survival and the survival of lung adenocarcinoma, mesothelioma, uveal melanoma, and breast cancer patients. We conclude that MAPK6 can promote cancer by activating AKT and that targeting MAPK6 may be effective in human cancers.

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

Cited by 69 publications

References 36 publications

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

NFKB1/NR3C1-MAPK4 axis regulates the pathology of acute lung injury

Oncogenic Activation of AKT by MAPK6

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