Ca2+/calmodulin-stimulated PDE1 regulates the beta-catenin/TCF signaling through PP2A B56 gamma subunit in proliferating vascular smooth muscle cells

Kye Im Jeon, Hirofumi Jono, Clint L. Miller, Yujun Cai, Soyeon Lim, Xuan Liu, Pingjin Gao, Jun Ichi Abe, Jian Dong Li, Chen Yan

Research output: Contribution to journalArticle

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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. Ca2+/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.

Original languageEnglish (US)
Pages (from-to)5026-5039
Number of pages14
JournalFEBS Journal
Volume277
Issue number24
DOIs
StatePublished - Dec 1 2010

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Type 1 Cyclic Nucleotide Phosphodiesterases
TCF Transcription Factors
Protein Phosphatase 2
Catenins
Phosphoric Diester Hydrolases
beta Catenin
Calmodulin
Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Cells
Glycogen Synthase Kinase 3
Isoenzymes
Phenotype
Enzyme inhibition
Phosphorylation
Muscle Proteins
Protein Stability
Phosphoprotein Phosphatases
Phosphatases

Keywords

  • PP2A
  • cyclic nucleotide
  • phosphodiesterase
  • vascular smooth muscle cells
  • β-catenin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Ca2+/calmodulin-stimulated PDE1 regulates the beta-catenin/TCF signaling through PP2A B56 gamma subunit in proliferating vascular smooth muscle cells. / Jeon, Kye Im; Jono, Hirofumi; Miller, Clint L.; Cai, Yujun; Lim, Soyeon; Liu, Xuan; Gao, Pingjin; Abe, Jun Ichi; Li, Jian Dong; Yan, Chen.

In: FEBS Journal, Vol. 277, No. 24, 01.12.2010, p. 5026-5039.

Research output: Contribution to journalArticle

Jeon, Kye Im ; Jono, Hirofumi ; Miller, Clint L. ; Cai, Yujun ; Lim, Soyeon ; Liu, Xuan ; Gao, Pingjin ; Abe, Jun Ichi ; Li, Jian Dong ; Yan, Chen. / Ca2+/calmodulin-stimulated PDE1 regulates the beta-catenin/TCF signaling through PP2A B56 gamma subunit in proliferating vascular smooth muscle cells. In: FEBS Journal. 2010 ; Vol. 277, No. 24. pp. 5026-5039.
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AU - Jeon, Kye Im

AU - Jono, Hirofumi

AU - Miller, Clint L.

AU - Cai, Yujun

AU - Lim, Soyeon

AU - Liu, Xuan

AU - Gao, Pingjin

AU - Abe, Jun Ichi

AU - Li, Jian Dong

AU - Yan, Chen

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