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Phosphorylation of beta‐catenin by PKA promotes vascular smooth muscle cell proliferation in response to purinergic receptor stimulation.
Author(s) -
Taurin Sebastien,
Dulin Nickolai O.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.329.1
Subject(s) - purinergic receptor , phosphorylation , vascular smooth muscle , microbiology and biotechnology , signal transduction , protein kinase a , chemistry , cell growth , beta catenin , biology , extracellular , endocrinology , biochemistry , wnt signaling pathway , smooth muscle
Extracellular ATP stimulates proliferation of vascular smooth muscle cells (VSMC) through activation of P2Y purinergic receptors. We have previously shown that a) ATP stimulates a transient activation of protein kinase A (PKA), which is required for maximal DNA synthesis in VSMC; and b) PKA can phosphorylate beta‐catenin at two novel sites (Ser552 and Ser675) in COS7‐overexpression cell model. Beta‐catenin is a signaling molecule which is regulated through degradation / stabilization mechanism, and which promotes cell proliferation by activation of T cell factor (TCF) transcription factors. In the present study, using the new phospho‐specific antibodies against pSer552 or pSer675 sites of beta‐catenin, we show that ATP can stimulate PKA‐dependent phosphorylation of endogenous beta‐catenin at both of these sites without affecting its expression levels in VSMC. This translates to a PKA‐dependent stimulation of TCF transcriptional activity, in part, through an increased association of phosphorylated (by PKA) beta‐catenin with TCF‐4. Using adenovirus‐mediated transduction of PKA inhibitor, PKI, or of dominant negative TCF‐4 mutant, we show that ATP stimulates cyclin D1 promoter activation, cyclin D1 protein expression and proliferation of VSMC – all in PKA‐ and TCF‐dependent manner. In conclusion, we show a critical role of ATP‐induced phosphorylation of beta‐catenin by PKA in proliferation of VSMC.