MAP4K4 is a novel MAPK/ERK pathway regulator required for lung adenocarcinoma maintenance
Xuan Gao1,2,3, Guangming Chen2,3, Chenxi Gao2,3
1Department of Respiratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China.
Abstract:
About 76% of patients with lung adenocarcinoma harbor activating mutations in the receptor tyrosine kinase (RTK)/RAS/RAF pathways, leading to aberrant activation of the mitogen-activated protein kinase (MAPK) pathways particularly the MAPK/ERK pathway. However, many lung adenocarcinomas lacking these genomic mutations also display significant MAPK pathway activation, suggesting that additional MAPK pathway alterations remain undetected. This study has identified serine/threonine kinase mitogen-activated protein 4 kinase 4 (MAP4K4) as a novel positive regulator of MAPK/ERK signaling in lung adenocarcinoma. The results showed that MAP4K4 was drastically elevated in lung adenocarcinoma independently of KRAS or EGFR mutation status. Knockdown of MAP4K4 inhibited proliferation, anchorage-independent growth and migration of lung adenocarcinoma cells, and also inhibited human lung adenocarcinoma xenograft growth and metastasis. Mechanistically, we found that MAP4K4 activated ERK through inhibiting protein phosphatase 2 activity. Our results further showed that downregulation of MAP4K4 prevented ERK reactivation in EGFR inhibitor erlotinib-treated lung adenocarcinoma cells. Together, our findings identify MAP4K4 as a novel MAPK/ERK pathway regulator in lung adenocarcinoma that is required for lung adenocarcinoma maintenance.
Insights
Researchers discovered that MAP4K4, a novel protein kinase, drives lung adenocarcinoma growth and metastasis by activating the MAPK/ERK pathway. Inhibiting MAP4K4 offers a potential therapeutic strategy for this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- Lung adenocarcinoma (LUAD) often exhibits activated mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling.
- While receptor tyrosine kinase (RTK)/RAS/RAF pathway mutations are common, many LUADs show MAPK pathway activation without these known drivers, indicating unidentified regulatory mechanisms.
Purpose of the Study:
- To identify novel regulators of MAPK/ERK signaling in lung adenocarcinoma.
- To investigate the role of serine/threonine kinase mitogen-activated protein 4 kinase 4 (MAP4K4) in LUAD pathogenesis.
Main Methods:
- Quantitative analysis of MAP4K4 expression in LUAD tissues.
- In vitro knockdown experiments using lung adenocarcinoma cell lines to assess proliferation, anchorage-independent growth, and migration.
- In vivo studies using human LUAD xenografts to evaluate tumor growth and metastasis.
- Mechanistic studies involving protein phosphatase 2 activity assays and analysis of ERK reactivation in response to EGFR inhibitor treatment.
Main Results:
- MAP4K4 expression is significantly elevated in lung adenocarcinoma, irrespective of KRAS or EGFR mutation status.
- MAP4K4 knockdown suppressed LUAD cell proliferation, growth, and migration, and reduced tumor growth and metastasis in vivo.
- MAP4K4 activates ERK signaling by inhibiting protein phosphatase 2 activity.
- Downregulation of MAP4K4 prevented ERK reactivation in cells treated with the EGFR inhibitor erlotinib.
Conclusions:
- MAP4K4 is a novel positive regulator of the MAPK/ERK pathway in lung adenocarcinoma.
- MAP4K4 is essential for maintaining lung adenocarcinoma progression and is a potential therapeutic target.
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