Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 17, Pages 6972-6985Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.005255
Keywords
profilin; PKA; cell adhesion; cell motility; phosphorylation; cytoskeleton; kinase signaling; Mena; vasodilator-stimulated phosphoprotein (VASP)
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Funding
- NCI, National Institutes of Health [2R01CA108607]
- National Science Foundation Predoctoral Fellowship [2012139050]
- NHLBI, National Institutes of Health [2T32HL076124]
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Dynamic regulation of the actin cytoskeleton is an essential feature of cell motility. Action of Enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP), a family of conserved actin-elongating proteins, is an important aspect of regulation of the actin cytoskeletal architecture at the leading edge that controls membrane protrusion and cell motility. In this study, we performed mutagenesis experiments in overexpression and knockdown-rescue settings to provide, for the first time, direct evidence of the role of the actin-binding protein profilin1 (Pfn1) in VASP-mediated regulation of cell motility. We found that VASP's interaction with Pfn1 is promoted by cell-substrate adhesion and requires down-regulation of PKA activity. Our experimental data further suggest that PKA-mediated Ser(137) phosphorylation of Pfn1 potentially negatively regulates the Pfn1-VASP interaction. Finally, Pfn1's ability to be phosphorylated on Ser(137) was partly responsible for the anti-migratory action elicited by exposing cells to a cAMP/PKA agonist. On the basis of these findings, we propose a mechanism of adhesion-protrusion coupling in cell motility that involves dynamic regulation of Pfn1 by PKA activity.
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