title: MAP4K4 is a novel MAPK/ERK pathway regulator required for lung adenocarcinoma maintenance.
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.
authors.affiliation: Department of Respiratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA, USA.|University of Pittsburgh Cancer Institute, PA, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA, USA.|University of Pittsburgh Cancer Institute, PA, USA.
authors.forename: Guangming
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA, USA.|University of Pittsburgh Cancer Institute, PA, USA.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Gao
authors.affiliation: University of Pittsburgh Dietrich School of Arts and Sciences, PA, USA.
authors.forename: Dennis Han
authors.initials: DH
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, PA, USA.
authors.forename: Shih-Fan
authors.initials: SF
authors.lastname: Kuan
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA, USA.|University of Pittsburgh Cancer Institute, PA, USA.
authors.forename: Laura P
authors.initials: LP
authors.lastname: Stabile
authors.affiliation: Department of Respiratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA, USA.|University of Pittsburgh Cancer Institute, PA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C117090:MAP4K4 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D054648:Protein Phosphatase 2; D016283:Proto-Oncogene Proteins p21(ras)
keywords: 
  EGFR
  ; 
  ERK
  ; MAP4K4; cell signaling; lung adenocarcinoma