Regulation of lung epithelial cell morphology by cAMP-dependent protein kinase type I isozyme.
Cell shape is mediated in part by the actin cytoskeleton and the actin-binding protein vinculin. These proteins in turn are regulated by protein phosphorylation. We assessed the contribution of cAMP-dependent protein kinase A isozyme I (PKA I) to lung epithelial morphology using the E10/E9 sibling cell lines. PKA I concentration is high in flattened, nontumorigenic E10 cells but low in their round E9 transformants. PKA I activity was lowered in E10 cells by stable transfection with a dominant negative RIalpha mutant of the PKA I regulatory subunit and was raised in E9 cells by stable transfection with a wild-type Calpha catalytic subunit construct. Reciprocal changes in morphology ensued. E10 cells became rounder and grew in colonies, their actin microfilaments were disrupted, and vinculin localization at cell-cell junctions was diminished. The converse occurred in E9 cells on elevating their PKA I content. Demonstration that PKA I is responsible for the dichotomy in these cellular behaviors suggests that manipulating PKA I concentrations in lung cancer would provide useful adjuvant therapy.
Porter
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SE
Department of Pharmaceutical Sciences and University of Colorado Cancer Center, University of Colorado Health Sciences Center, 420 East Ninth Avenue, Denver, CO 80262, USA.
Dwyer-Nield
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LD
Malkinson
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AM
D000199:Actins / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D002461:Cell Line, Transformed; D048429:Cell Size / Q000235:genetics; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D005799:Genes, Dominant; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000201:enzymology*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D014162:Transfection; D016596:Vinculin / Q000378:metabolism
D000199:Actins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D007527:Isoenzymes; C517835:Prkar1a protein, mouse; D016596:Vinculin; D017868:Cyclic AMP-Dependent Protein Kinases