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Protein Kinase A Effects of an Expressed PRKAR1A Mutation Associated with Aggressive Tumors

¹ Section on Endocrinology and Genetics, Program in Developmental Endocrinology and Genetics, and ² Section on Organelle Biology, Program in Cell Biology and Metabolism, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland; ³ Institut National de la Santé et de la Recherche Médicale U567, Département d'Endocrinologie, Métabolisme and Cancer, Institut Cochin; ⁴ Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104; and ⁵ Centre de Référence des Maladies Rares de la Surrénale, Service d'Endocrinologie, Hôpital Cochin, Université Paris 5, Paris, France

Requests for reprints: Constantine A. Stratakis, Section on Endocrinology and Genetics, Program in Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892. Phone: 301-496-4686; Fax: 301-402-0574; E-mail: stratakc{at}mail.nih.gov.

Key Words: Carney complex • primary pigmented nodular adrenocortical disease • expressed mutations • multiple endocrine neoplasia • cyclic AMP-dependent protein kinase

Most PRKAR1A tumorigenic mutations lead to nonsense mRNA that is decayed; tumor formation has been associated with an increase in type II protein kinase A (PKA) subunits. The IVS6+1G>T PRKAR1A mutation leads to a protein lacking exon 6 sequences [R1184-236 (R16)]. We compared in vitro R16 with wild-type (wt) R1. We assessed PKA activity and subunit expression, phosphorylation of target molecules, and properties of wt-R1 and mutant (mt) R1; we observed by confocal microscopy R1 tagged with green fluorescent protein and its interactions with Cerulean-tagged catalytic subunit (C). Introduction of the R16 led to aberrant cellular morphology and higher PKA activity but no increase in type II PKA subunits. There was diffuse, cytoplasmic localization of R1 protein in wt-R1– and R16-transfected cells but the former also exhibited discrete aggregates of R1 that bound C; these were absent in R16-transfected cells and did not bind C at baseline or in response to cyclic AMP. Other changes induced by R16 included decreased nuclear C. We conclude that R16 leads to increased PKA activity through the mt-R1 decreased binding to C and does not involve changes in other PKA subunits, suggesting that a switch to type II PKA activity is not necessary for increased kinase activity or tumorigenesis. [Cancer Res 2008;68(9):3133–41]

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