Tumor Necrosis Factor-α Stimulates Focal Adhesion Kinase Activity Required for Mitogen-activated Kinase-associated Interleukin 6 Expression
| Autor: | Honggang Yu, Alok Tomar, Dan A. Hanson, Ssang-Taek Lim, John Molina, Sean Uryu, Satyajit Sujit Kumar Mitra, Shihe Hou, David D. Schlaepfer, Yangmi Lim |
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| Rok vydání: | 2007 |
| Předmět: |
MAPK/ERK pathway
Proline Biochemistry Small hairpin RNA Focal adhesion Mice Cell Line Tumor Animals Kinase activity Molecular Biology Mice Knockout PTK2B biology Interleukin-6 Tumor Necrosis Factor-alpha Kinase Chemistry NF-kappa B Cell Biology Fibroblasts Cell biology Enzyme Activation src-Family Kinases Focal Adhesion Protein-Tyrosine Kinases Mitogen-activated protein kinase Cancer research biology.protein Tyrosine RNA Interference Mitogen-Activated Protein Kinases biological phenomena cell phenomena and immunity Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Journal of Biological Chemistry. 282:17450-17459 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m610672200 |
| Popis: | Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase that promotes cell migration, survival, and gene expression. Here we show that FAK signaling is important for tumor necrosis factor-alpha (TNFalpha)-induced interleukin 6 (IL-6) mRNA and protein expression in breast (4T1), lung (A549), prostate (PC-3), and neural (NB-8) tumor cells by FAK short hairpin RNA knockdown and by comparisons of FAK-null (FAK(-/-)) and FAK(+/+) mouse embryo fibroblasts. FAK promoted TNFalpha-stimulated MAPK activation needed for maximal IL-6 production. FAK was not required for TNFalpha-mediated nuclear factor-kappaB or c-Jun N-terminal kinase activation. TNFalpha-stimulated FAK catalytic activation and IL-6 production were inhibited by FAK N-terminal but not FAK C-terminal domain overexpression. Analysis of FAK(-/-) fibroblasts stably reconstituted with wild type or various FAK point mutants showed that FAK catalytic activity, Tyr-397 phosphorylation, and the Pro-712/713 proline-rich region of FAK were required for TNFalpha-stimulated MAPK activation and IL-6 production. Constitutively activated MAPK kinase-1 (MEK1) expression in FAK(-/-) and A549 FAK short hairpin RNA-expressing cells rescued TNFalpha-stimulated IL-6 production. Inhibition of Src protein-tyrosine kinase activity or mutation of Src phosphorylation sites on FAK (Tyr-861 or Tyr-925) did not affect TNFalpha-stimulated IL-6 expression. Moreover, analyses of Src(-/-), Yes(-/-), and Fyn(-/-) fibroblasts showed that Src expression was inhibitory to TNFalpha-stimulated IL-6 production. These studies provide evidence for a novel Src-independent FAK to MAPK signaling pathway regulating IL-6 expression with potential importance to inflammation and tumor progression. |
| Databáze: | OpenAIRE |
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