A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy

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Abstract
We describe a novel signaling mechanism mediated by the G‐protein‐coupled receptor (GPCR) angiotensin II (Ang II) type 2 receptor (AT2). Yeast two‐hybrid studies and affinity column binding assay show that the isolated AT2 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 AT2 at the plasma membrane, then drives AT2 and PLZF to internalize. PLZF slowly emerges in the nucleus whereas AT2 accumulates in the perinuclear region. Nuclear PLZF binds to a consensus sequence of the phosphatidylinositol‐3 kinase p85α subunit (p85α PI3K) gene. AT2 enhances expression of p85α PI3K followed by enhanced p70S6 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 AT2, PLZF and p85α PI3K may explain the absence of a cardiac hypertrophic response in AT2 gene‐deleted mice.