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GIT1 mediated HDAC5 phosphorylation by angiotensin II through Src, PLCγ, and CamKII
Author(s) -
Pang Jinjiang,
Yan Chen,
Massett Michael P,
Berk Bradford C
Publication year - 2007
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.21.6.a1151-a
Subject(s) - histone deacetylase 5 , phosphorylation , autophosphorylation , microbiology and biotechnology , signal transduction , angiotensin ii , biology , gene knockdown , kinase , medicine , cancer research , endocrinology , protein kinase a , receptor , histone deacetylase , biochemistry , histone , apoptosis , gene
Class II histone deacetylase 5 (HDAC5) acts as an antagonist of pathological signaling pathways, leading to cardiac hypertrophy. Phosphorylation of HDAC5 by Ca 2+ ‐calmodulin–dependent proteinkinase II (CamKII) promotes shuttling of HDAC5 from the nucleus to the cytoplasm; derepressing HDAC5 target genes and promoting cardiac hypertrophy. Angiotensin II (AngII) plays an important role in myocyte hypertrophy. In vascular smooth muscle cells (VSMC), AngII signaling leads to phosphorylation of G‐protein‐coupled receptor ‐kinase interacting protein 1 (GIT1) by c‐Src, resulting in activation of PLCγ and subsequent autophosphorylation of CamKII. Therefore, we hypothesized that GIT1 mediates HDAC5 phosphorylation by AngII and induces hypertrophy of VSMC. AngII increased phosphorylation of HDAC5 time dependently in VSMC. Ang II increased the association of CamKII, HDAC5 and 14‐3‐3. Knockdown of GIT1 with antisense GIT1 oligonucleotides inhibited the HDAC5 phosphorylation. CamKII inhibitor, KN93 decreased phosphorylation of HDAC5. U73122 (PLCγ inhibitor), PP2 (Src inhibitor) and adenovirus dominant‐negative Src (kinase negative Src) dose dependently attenuated phosphorylation of HDAC5 by AngII demonstrating the involvement of PLCγ and c‐Src in this pathway. In conclusion, GIT1 plays an important role in AngII stimulated phosphorylation of HDAC5 via a pathway involving Src, PLCγ and CamKII in VSMC.