β-Arrestin1 Interacts with the Catalytic Domain of the Tyrosine Kinase c-SRC

By W. Miller, Stuart Maudsley, Seungkirl Ahn, K. Khan, L. Luttrell, R. J. Lefkowitz. Journal of Biological Chemistry, 2000

194 citations recorded by the source corpus.

β-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 β2-adrenergic receptor in a β-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 β-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 β-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 β-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 β2-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 β-arrestin1/c-SRC interaction but also implicate β-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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8dd8685c4c4bf4c1626f4e5fa2983a3f86771830

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In Cellular and Molecular Neuroscience

1. R. J. Lefkowitz
2. Sudha K. Shenoy
3. L. Luttrell
4. Éric Reiter
5. Brian K. Kobilka

In Molecular Biology

1. R. J. Lefkowitz
2. Sudha K. Shenoy
3. L. Luttrell
4. Éric Reiter
5. Seungkirl Ahn
6. S. Rajagopal
7. Brian K. Kobilka

Citations in the corpus

• The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. (2002, background): “Expression of a mutant Src protein that contains only a catalytically inactive SH1 domain but still binds avidly to β- arrestin selectively inhibits β2-adrenergic-receptor-stimulated tyrosine phosphorylation of dynamin and receptor internalization (Miller et al., 2000).”
• Multifaceted roles of β-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling (2003, background): “This mutant, called SH1KD, acts as a dominant-negative with respect to processes requiring both Src activity and β -arrestin recruitment [85].”