Inhibition of PKA Blocks Fibroblast Migration in Response to Growth Factors

Cell migration requires precise coordination of many signaling pathways to achieve directed motility. We report here that NIH3T3 fibroblasts expressing a dominant negative PKA subunit (dnPKA) show diminished migration in response to serum or growth factors. This effect is not a general effect on cel...

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Bibliographic Details
Published in:Experimental cell research 2001-11, Vol.270 (2), p.214-222
Main Authors: Edin, Matthew L., Howe, Alan K., Juliano, Rudy L.
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Butadienes - pharmacology
Chemotaxis - drug effects
Chemotaxis - physiology
Chromones - pharmacology
Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors
Cyclic AMP-Dependent Protein Kinases - metabolism
Enzyme Inhibitors - pharmacology
Epidermal Growth Factor - pharmacology
Mice
Mitogen-Activated Protein Kinases - metabolism
Morpholines - pharmacology
Nitriles - pharmacology
Platelet-Derived Growth Factor - pharmacology
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Summary:Cell migration requires precise coordination of many signaling pathways to achieve directed motility. We report here that NIH3T3 fibroblasts expressing a dominant negative PKA subunit (dnPKA) show diminished migration in response to serum or growth factors. This effect is not a general effect on cell motility, but rather a decreased capacity to enhance migration in response to stimuli. Control (neo) and dnPKA cells show very similar haptotactic migration toward fibronectin, but dnPKA cells show reduced stimulation of migration in response to EGF/PDGF or serum. These effects were not due to alterations in cell growth or adhesion to fibronectin. Forskolin, which elevates cyclic adenosine monophosphate (cAMP) levels, dramatically inhibited neo cell motility in a scrape migration assay, although dnPKA cell migration was unaffected. The MEK selective inhibitor U0126 and the phosphatidyl-inositol-3 kinase (PI3K) inhibitor LY294002 inhibited migrating neo cells and were able to further inhibit residual dnPKA cell migration. Our data show that intermediate or well-controlled levels of PKA activity are required for optimal growth factor-stimulated migration in fibroblasts. PKA may play an important role in the signaling processes that lead to motility.
ISSN:0014-4827
1090-2422
DOI:10.1006/excr.2001.5345