Phosphorylation of β-catenin by PKA promotes ATP-induced proliferation of vascular smooth muscle cells
- 1 May 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Cell Physiology
- Vol. 294 (5), C1169-C1174
- https://doi.org/10.1152/ajpcell.00096.2008
Abstract
Extracellular ATP stimulates proliferation of vascular smooth muscle cells (VSMC) through activation of G protein-coupled P2Y purinergic receptors. We have previously shown that ATP stimulates a transient activation of protein kinase A (PKA), which, together with the established mitogenic signaling of purinergic receptors, promotes proliferation of VSMC (Hogarth DK, Sandbo N, Taurin S, Kolenko V, Miano JM, Dulin NO. Am J Physiol Cell Physiol 287: C449–C456, 2004). We also have shown that PKA can phosphorylate β-catenin at two novel sites (Ser552 and Ser675) in vitro and in overexpression cell models (Taurin S, Sandbo N, Qin Y, Browning D, Dulin NO. J Biol Chem 281: 9971–9976, 2006). β-Catenin promotes cell proliferation by activation of a family of T-cell factor (TCF) transcription factors, which drive the transcription of genes implicated in cell cycle progression including cyclin D1. In the present study, using the phosphospecific antibodies against phospho-Ser552 or phospho-Ser675 sites of β-catenin, we show that ATP can stimulate PKA-dependent phosphorylation of endogenous β-catenin at both of these sites without affecting its expression levels in VSMC. This translates to a PKA-dependent stimulation of TCF transcriptional activity through an increased association of phosphorylated (by PKA) β-catenin with TCF-4. Using the PKA inhibitor PKI or dominant negative TCF-4 mutant, we show that ATP-induced cyclin D1 promoter activation, cyclin D1 protein expression, and proliferation of VSMC are all dependent on PKA and TCF activities. In conclusion, we show a novel mode of regulation of endogenous β-catenin through its phosphorylation by PKA, and we demonstrate the importance of this mechanism for ATP-induced proliferation of VSMC.Keywords
This publication has 32 references indexed in Scilit:
- Downregulation of smooth muscle α-actin expression by bacterial lipopolysaccharideCardiovascular Research, 2007
- PKC-δ and CaMKII-δ2 mediate ATP-dependent activation of ERK1/2 in vascular smooth muscleAmerican Journal of Physiology-Cell Physiology, 2004
- Betacellulin and Amphiregulin Induce Upregulation of Cyclin D1 and DNA Synthesis Activity Through Differential Signaling Pathways in Vascular Smooth Muscle CellsCirculation Research, 2003
- Functional P2Y 2 Nucleotide Receptors Mediate Uridine 5′-Triphosphate–Induced Intimal Hyperplasia in Collared Rabbit Carotid ArteriesCirculation, 2002
- Glycogen Synthase Kinase-3βCirculation Research, 2002
- A Role for the β-Catenin/T-Cell Factor Signaling Cascade in Vascular RemodelingCirculation Research, 2002
- P2 receptors: new potential players in atherosclerosisBritish Journal of Pharmacology, 2002
- Potential therapeutic targets in the rapidly expanding field of purinergic signallingClinical Medicine, 2002
- Extracellular ATP: A Growth Factor for Vascular Smooth Muscle CellsGeneral Pharmacology: The Vascular System, 1998
- Extracellular ATP and ADP stimulate proliferation of porcine aortic smooth muscle cellsJournal of Cellular Physiology, 1992