Open AccessMAP 4K4 is a novel MAPK / ERK pathway regulator required for lung adenocarcinoma maintenance
Author(s) -
Gao Xuan,
Chen Guangming,
Gao Chenxi,
Zhang Dennis Han,
Kuan ShihFan,
Stabile Laura P.,
Liu Guoxiang,
Hu Jing
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12055
Subject(s) - mapk/erk pathway , cancer research , adenocarcinoma , protein kinase a , signal transduction , kinase , biology , medicine , microbiology and biotechnology , cancer
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 ( MAP 4K4) as a novel positive regulator of MAPK / ERK signaling in lung adenocarcinoma. The results showed that MAP 4K4 was drastically elevated in lung adenocarcinoma independently of KRAS or EGFR mutation status. Knockdown of MAP 4K4 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 MAP 4K4 activated ERK through inhibiting protein phosphatase 2 activity. Our results further showed that downregulation of MAP 4K4 prevented ERK reactivation in EGFR inhibitor erlotinib‐treated lung adenocarcinoma cells. Together, our findings identify MAP 4K4 as a novel MAPK / ERK pathway regulator in lung adenocarcinoma that is required for lung adenocarcinoma maintenance.