A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy.
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 p85 alpha subunit (p85 alpha PI3K) gene. AT(2) enhances expression of p85 alpha 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 p85 alpha PI3K may explain the absence of a cardiac hypertrophic response in AT(2) gene-deleted mice.
Senbonmatsu
Takaaki
T
Departments of Biochemistry, Pharmacology, Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Saito
Takako
T
Landon
Erwin J
EJ
Watanabe
Otsu
O
Price
Edward
E
Roberts
Richard L
RL
Imboden
Hans
H
Fitzgerald
Trinita G
TG
Gaffney
F Andrew
FA
Inagami
Tadashi
T
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006332:Cardiomegaly / Q000235:genetics* / Q000503:physiopathology* / Q000517:prevention & control; D003001:Cloning, Molecular; D017124:Conserved Sequence; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D021381:Protein Transport; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D044139:Receptor, Angiotensin, Type 2; D019893:Ribosomal Protein S6 Kinases; D014157:Transcription Factors; C513267:Zbtb16 protein, mouse; C092037:ZBTB16 protein, human