Title
<tex>$\beta$</tex>-arrestin1 interacts with the catalytic domain of the tyrosine kinase c-SRC : role of <tex>$\beta$</tex>-arrestin1-dependent targeting of c-SRC in receptor endocytosis <tex>$\beta$</tex>-arrestin1 interacts with the catalytic domain of the tyrosine kinase c-SRC : role of <tex>$\beta$</tex>-arrestin1-dependent targeting of c-SRC in receptor endocytosis
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
Baltimore, Md ,
Subject
Chemistry
Biology
Source (journal)
Journal of biological chemistry. - Baltimore, Md
Volume/pages
275(2000) :15 , p. 11312-11319
ISSN
0021-9258
ISI
000086466600085
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
beta-Arrestins can act as adapter molecules, coupling G-protein-coupled receptors to proteins involved in mitogenic as well as endocytic pathways. We have previously identified c-SRC as a molecule that is rapidly recruited to the beta 2-adrenergic receptor in a beta-arrestin1-dependent manner, Recruitment of c-SRC to the receptor appears to be involved in pathways leading to receptor internalization and mitogen-activated protein kinase activation. This recruitment of c-SRC to the receptor involves an interaction between the amino-terminal proline-rich region of beta-arrestin1 and the Src homology 3 (SH3) domain of c-SRC, but deletion of the proline-rich domain does not totally ablate the interaction. We have found that a major interaction also exists between beta-arrestin1 and the catalytic or kinase domain (SH1) of c-SRC, We therefore hypothesized that a catalytically inactive mutant of the isolated catalytic subunit, SH1 (kinase dead) (SH1(KD)), would specifically block those cellular actions of c-SRC that are mediated by beta-arrestin1 recruitment to the G-protein-coupled receptor. In contrast, the majority of cellular phosphorylations catalyzed by c-SRC, which do not involve interaction with the SH1 domain, would be predicted to be unaffected. The SH1(KD) mutant did indeed block beta 2-adrenergic receptor internalization and receptor-stimulated tyrosine phosphorylation of dynamin, actions previously shown to be c-SRC-dependent, In contrast, SAM-68 and whole cell tyrosine phosphorylation by c-SRC was unaffected, indicating that the SH1(KD) mutant did not inhibit c-SRC tyrosine kinase activity in general. These results not only clarify the nature of the beta-arrestin1/c-SRC interaction but also implicate beta-arrestin1 as an important mediator of receptor internalization by recruiting tyrosine kinase activity to the cell surface to phosphorylate key endocytic intermediates, such as dynamin.
E-info
https://repository.uantwerpen.be/docman/iruaauth/747dc7/d7c9078.pdf
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