Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor γ2 expression

Young Ho Ahn, Yanan Yang, Don L. Gibbons, Chad J. Creighton, Fei Yang, Ignacio I. Wistuba, Wei Lin, Nishan Thilaganathan, Cristina A. Alvarez, Jonathon Roybal, Elizabeth J. Goldsmith, Cathy Tournier, Jonathan M. Kurie

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

MAP2K4 encodes a dual-specificity kinase (mitogen-activated protein kinase kinase 4, or MKK4) that is mutated in a variety of human malignancies, but the biochemical properties of the mutant kinases and their roles in tumorigenesis have not been fully elucidated. Here we showed that 8 out of 11 cancer-associated MAP2K4 mutations reduce MKK4 protein stability or impair its kinase activity. On the basis of findings from bioinformatic studies on human cancer cell lines with homozygous MAP2K4 loss, we posited that MKK4 functions as a tumor suppressor in lung adenocarcinomas that develop in mice owing to expression of mutant Kras and Tp53. Conditional Map2k4 inactivation in the bronchial epithelium of mice had no discernible effect alone but increased the multiplicity and accelerated the growth of incipient lung neoplasias induced by oncogenic Kras. MKK4 suppressed the invasion and metastasis of Kras-Tp53-mutant lung adenocarcinoma cells. MKK4 deficiency increased peroxisomal proliferator-activated receptor γ2 (PPARγ2) expression through noncanonical MKK4 substrates, and PPARγ2 enhanced tumor cell invasion. We conclude that Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing PPARγ2 levels.

Original languageEnglish (US)
Pages (from-to)4270-4285
Number of pages16
JournalMolecular and cellular biology
Volume31
Issue number21
DOIs
StatePublished - Nov 1 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Ahn, Y. H., Yang, Y., Gibbons, D. L., Creighton, C. J., Yang, F., Wistuba, I. I., Lin, W., Thilaganathan, N., Alvarez, C. A., Roybal, J., Goldsmith, E. J., Tournier, C., & Kurie, J. M. (2011). Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor γ2 expression. Molecular and cellular biology, 31(21), 4270-4285. https://doi.org/10.1128/MCB.05562-11