Regulation of actin function by protein kinase A-mediated phosphorylation of Limk1.
Proper regulation of the cAMP-dependent protein kinase (protein kinase A, PKA) is necessary for cellular homeostasis, and dysregulation of this kinase is crucial in human disease. Mouse embryonic fibroblasts (MEFs) lacking the PKA regulatory subunit Prkar1a show altered cell morphology and enhanced migration. At the molecular level, these cells showed increased phosphorylation of cofilin, a crucial modulator of actin dynamics, and these changes could be mimicked by stimulating the activity of PKA. Previous studies of cofilin have shown that it is phosphorylated primarily by the LIM domain kinases Limk1 and Limk2, which are under the control of the Rho GTPases and their downstream effectors. In Prkar1a(-/-) MEFs, neither Rho nor Rac was activated; rather, we showed that PKA could directly phosphorylate Limk1 and thus enhance the phosphorylation of cofilin. These data indicate that PKA is crucial in cell morphology and migration through its ability to modulate directly the activity of LIM kinase.
Nadella
Kiran S
KS
Department of Molecular Virology, Immunology & Medical Genetics, The Ohio State University, 420 West 12th Avenue, TMRF 544, Columbus, Ohio 43210, USA.
Saji
Motoyasu
M
Jacob
Naduparambil K
NK
Pavel
Emilia
E
Ringel
Matthew D
MD
Kirschner
Lawrence S
LS
D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation
D000199:Actins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse; D054461:Lim Kinases; C515893:Limk1 protein, mouse