title: Ca2+/calmodulin-stimulated PDE1 regulates the beta-catenin/TCF signaling through PP2A B56 gamma subunit in proliferating vascular smooth muscle cells.
abstract: The phenotypic change of vascular smooth muscle cells (VSMCs), from a 'contractile' phenotype to a 'synthetic' phenotype, is crucial for pathogenic vascular remodeling in vascular diseases such as atherosclerosis and restenosis. Ca(2+)/calmodulin-stimulated phosphodiesterase 1 (PDE1) isozymes, including PDE1A and PDE1C, play integral roles in regulating the proliferation of synthetic VSMCs. However, the underlying molecular mechanism(s) remain unknown. In this study, we explore the role and mechanism of PDE1 isoforms in regulating β-catenin/T-cell factor (TCF) signaling in VSMCs, a pathway important for vascular remodeling through promoting VSMC growth and survival. We found that inhibition of PDE1 activity markedly attenuated β-catenin/TCF signaling by downregulating β-catenin protein. The effect of PDE1 inhibition on β-catenin protein reduction is exerted via promoting glycogen synthase kinase 3 (GSK3)β activation, β-catenin phosphorylation and subsequent β-catenin protein degradation. Moreover, PDE1 inhibition specifically upregulated phosphatase protein phosphatase 2A (PP2A) B56γ subunit gene expression, which is responsible for the effects of PDE1 inhibition on GSK3β and β-catenin/TCF signaling. Furthermore, the effect of PDE1 inhibition on β-catenin was specifically mediated by PDE1A but not PDE1C isozyme. Interestingly, in synthetic VSMCs, PP2A B56γ, phospho-GSK3β and phospho-β-catenin were all found in the nucleus, suggesting that PDE1A regulates nuclear β-catenin protein stability through the nuclear PP2A-GSK3β-β-catenin signaling axis. Taken together, these findings provide direct evidence for the first time that PP2A B56γ is a critical mediator for PDE1A in the regulation of β-catenin signaling in proliferating VSMCs.
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Kye-Im
authors.initials: KI
authors.lastname: Jeon
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Clint L
authors.initials: CL
authors.lastname: Miller
authors.forename: Yujun
authors.initials: Y
authors.lastname: Cai
authors.forename: Soyeon
authors.initials: S
authors.lastname: Lim
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: Pingjin
authors.initials: P
authors.lastname: Gao
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Abe
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000378:metabolism*; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051381:Rats; D051820:TCF Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D002147:Calmodulin; D051820:TCF Transcription Factors; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D002118:Calcium