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A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy
Author(s) -
Senbonmatsu Takaaki,
Saito Takako,
Landon Erwin J.,
Watanabe Otsu,
Price Edward,
Roberts Richard L.,
Imboden Hans,
Fitzgerald Trinita G.,
Gaffney F.Andrew,
Inagami Tadashi
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg637
Subject(s) - biology , signal transduction , angiotensin ii , receptor , renin–angiotensin system , cardiac hypertrophy , microbiology and biotechnology , medicine , endocrinology , muscle hypertrophy , genetics , blood pressure
We describe a novel signaling mechanism mediated by the G‐protein‐coupled receptor (GPCR) angiotensin II (Ang II) type 2 receptor (AT 2 ). Yeast two‐hybrid studies and affinity column binding assay show that the isolated AT 2 C‐terminus binds to the transcription factor promyelocytic zinc finger protein (PLZF). Cellular studies employing confocal microscopy show that Ang II stimulation induces cytosolic PLZF to co‐localize with AT 2 at the plasma membrane, then drives AT 2 and PLZF to internalize. PLZF slowly emerges in the nucleus whereas AT 2 accumulates in the perinuclear region. Nuclear PLZF binds to a consensus sequence of the phosphatidylinositol‐3 kinase p85α subunit (p85α PI3K) gene. AT 2 enhances expression of p85α PI3K followed by enhanced p70 S6 kinase, essential to protein synthesis. An inactive mutant of PLZF abolishes this effect. PLZF is expressed robustly in the heart in contrast to many other tissues. This cardiac selective pathway involving AT 2 , PLZF and p85α PI3K may explain the absence of a cardiac hypertrophic response in AT 2 gene‐deleted mice.