title: Protein kinase A activation enhances β-catenin transcriptional activity through nuclear localization to PML bodies.
abstract: The Protein Kinase A (PKA) and Wnt signaling cascades are fundamental pathways involved in cellular development and maintenance. In the osteoblast lineage, these pathways have been demonstrated functionally to be essential for the production of mineralized bone. Evidence for PKA-Wnt crosstalk has been reported both during tumorigenesis and during organogenesis, and the nature of the interaction is thought to rely on tissue and cell context. In this manuscript, we analyzed bone tumors arising from mice with activated PKA caused by mutation of the PKA regulatory subunit Prkar1a. In primary cells from these tumors, we observed relocalization of β-catenin to intranuclear punctuate structures, which were identified as PML bodies. Cellular redistribution of β-catenin could be recapitulated by pharmacologic activation of PKA. Using 3T3-E1 pre-osteoblasts as a model system, we found that PKA phosphorylation sites on β-catenin were required for nuclear re-localization. Further, β-catenin's transport to the nucleus was accompanied by an increase in canonical Wnt-dependent transcription, which also required the PKA sites. PKA-Wnt crosstalk in the cells was bi-directional, including enhanced interactions between β-catenin and the cAMP-responsive element binding protein (CREB) and transcriptional crosstalk between the Wnt and PKA signaling pathways. Increases in canonical Wnt/β-catenin signaling were associated with a decrease in the activity of the non-canonical Wnt/Ror2 pathway, which has been shown to antagonize canonical Wnt signaling. Taken together, this study provides a new understanding of the complex regulation of the subcellular distribution of β-catenin and its differential protein-protein interaction that can be modulated by PKA signaling.
authors.affiliation: Department of Molecular, Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Molecular, Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Emilia
authors.initials: E
authors.lastname: Mahoney
authors.affiliation: Department of Molecular, Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Tao
authors.initials: T
authors.lastname: Zuo
authors.affiliation: Department of Molecular, Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Parmeet K
authors.initials: PK
authors.lastname: Manchanda
authors.affiliation: Department of Molecular, Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Ramana V
authors.initials: RV
authors.lastname: Davuluri
authors.affiliation: Department of Molecular, Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, United States of America; Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kirschner
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics* / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse