Prolyl hydroxylase 2: a novel regulator of β2 -adrenoceptor internalization.
Adrenergic receptor (AR)-mediated signalling is modulated by oxygen levels. Prolyl hydroxylases (PHDs) are crucial for intracellular oxygen sensing and organism survival. However, it remains to be clarified whether or how PHDs are involved in the regulation of β(2) -adrenoceptor (β(2) -AR) signalling. Here we show that PHD2 can modulate the rate of β(2) -AR internalization through interactions with β-arrestin 2. PHD2 hydroxylates β-arrestin 2 at the proline (Pro)(176), Pro(179) and Pro(181) sites, which retards the recruitment of β-arrestin 2 to the plasma membrane and inhibits subsequent co-internalization with β(2) -AR into the cytosol. β(2) -AR internalization is critical to control the temporal and spatial aspects of β(2) -AR signalling. Identifying novel regulators of β(2) -AR internalization will enable us to develop new strategies to manipulate receptor signalling and provide potential targets for drug development in the prevention and treatment of diseases associated with β(2) -AR signalling dysregulation.
Key Laboratory of Arrhythmias, Ministry of Education, China (East Hospital, Tongji University School of Medicine), Shanghai, China.
Biao
B
Yan
Zhaoxia
Z
Huo
Ying
Y
Liu
Xiaoping
X
Lin
Jun
J
Li
Luying
L
Peng
Hong
H
Zhao
Zhao-Nian
ZN
Zhou
Xingqun
X
Liang
Yi
Y
Liu
Weidong
W
Zhu
Dandan
D
Liang
Li
L
Li
Yunfu
Y
Sun
Jianmin
J
Cui
Yi-Han
YH
Chen
D019390:Arrestins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; D019390:Arrestins; D034741:RNA, Small Interfering; D018343:Receptors, Adrenergic, beta-2; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
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