期刊
CELLULAR SIGNALLING
卷 21, 期 1, 页码 103-110出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2008.09.013
关键词
G protein-coupled receptors; AT1R; beta arrestins; c-Src; AP-2; Clathrin; EGF receptor
类别
资金
- Canadian Institutes of Health Research (CIHR)
- CIHR
- McGill University Health Center Research Institute (MUHC-RI)
- Fonds de la Recherche en Sante du Quebec (FRSQ)
Clathrin-mediated endocytosis is a complex process regulated at many different levels. We showed previously that activation of the angiotensin type 1 receptor (AT1R), which belongs to the G protein-coupled receptor (GPCR) family, leads to c-Src-dependent tyrosine phosphorylation of beta 2-adaptin, a subunit of the clathrin adaptor AP-2. The phosphorylation of beta 2-adaptin on tyrosine residue 737 (Y737) negatively regulates its interaction with beta arrestin, another important clathrin adaptor for GPCR internalization. Here we sought to determine whether AP-2 phosphorylation represents a general mechanism for different receptors internalizing through the clathrin pathway. Using a specifically designed antibody against the phosphorylated form of Y737 on beta 2-adaptin, we demonstrate that this residue is phosphorylated by AT1R in different cell types like HEK293, COS-7 and vascular smooth muscle cells. Using RNA interference approaches, we reveal that this agonist-mediated event is both beta arrestin- and c-Src-dependent, and that it occurs at the plasma membrane in clathrin-coated vesicles (CCVs). We further show that this is not only a common event employed by other GPCRs like the beta 2-adrenergic, vasopressin V2, bradykinin type 2, platelet-activating factor and endothelin A receptors but that the epidermal growth factor receptor is capable of eliciting the phosphorylation of AP-2 in CCVs. Our results imply that tyrosine phosphorylation of Y737 on beta 2-adaptin is a common regulatory mechanism employed by different receptors undergoing clathrin-dependent endocytosis, and suggest a wider function for this event than originally anticipated. (C) 2008 Elsevier Inc. All rights reserved.
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