Angiotensin II type 2 receptor mediates programmed cell death.
The function of the recently discovered angiotensin II type 2 (AT2) receptor remains elusive. This receptor is expressed abundantly in fetus, but scantily in adult tissues except brain, adrenal medulla, and atretic ovary. In this study, we demonstrated that this receptor mediates programmed cell death (apoptosis). We observed this effect in PC12W cells (rat pheochromocytoma cell line) and R3T3 cells (mouse fibroblast cell line), which express abundant AT2 receptor but not AT1 receptor. The cellular mechanism appears to involve the dephosphorylation of mitogen-activated protein kinase (MAP kinase). Vanadate, a protein-tyrosine-phosphatase inhibitor, attenuated the dephosphorylation of MAP kinases by the AT2 receptor and restored the apoptotic changes. Antisense oligonucleotide to MAP kinase phosphatase 1 inhibited the AT2 receptor-mediated MAP kinase dephosphorylation and blocked the AT2 receptor-mediated apoptosis. These results suggest that protein-tyrosine-phosphatase, including MAP kinase phosphatase 1 activated by the AT2 receptor, is involved in apoptosis. We hypothesize that this apoptotic function of the AT2 receptor may play an important role in developmental biology and pathophysiology.
Yamada
T
T
Falk Cardiovascular Research Center, Stanford University School of Medicine, CA 94305-5246, USA.
Horiuchi
M
M
Dzau
V J
VJ
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D017874:Immediate-Early Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D011945:Receptors, Angiotensin / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D014162:Transfection
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D009414:Nerve Growth Factors; D016376:Oligonucleotides, Antisense; D011945:Receptors, Angiotensin; D011994:Recombinant Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases