beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins.
Abstract
One aspect of the function of the beta-arrestins is to serve as scaffold or adapter
molecules coupling G-protein coupled receptors (GPCRs) to signal transduction pathways
distinct from traditional second messenger pathways. Here we report the identification
of Dishevelled 1 and Dishevelled 2 (Dvl1 and Dvl2) as beta-arrestin1 (betaarr1) interacting
proteins. Dvl proteins participate as key intermediates in signal transmission from
the seven membrane-spanning Frizzled receptors leading to inhibition of glycogen synthase
kinase-3beta (GSK-3beta), stabilization of beta-catenin, and activation of the lymphoid
enhancer factor (LEF) transcription factor. We find that phosphorylation of Dvl strongly
enhances its interaction with betaarr1, suggesting that regulation of Dvl phosphorylation
and subsequent interaction with betaarr1 may play a key role in the activation of
the LEF transcription pathway. Because coexpression of the Dvl kinases, CK1epsilon
and PAR-1, with Dvl synergistically activates LEF reporter gene activity, we reasoned
that coexpression of betaarr1 with Dvl might also affect LEF-dependent gene activation.
Interestingly, whereas betaarr1 or Dvl alone leads to low-level stimulation of LEF
(2- to 5-fold), coexpression of betaarr1 with either Dvl1 or Dvl2 leads to a synergistic
activation of LEF (up to 16-fold). Additional experiments with LiCl as an inhibitor
of GSK-3beta kinase activity indicate that the step affected by betaarr1 is upstream
of GSK-3beta and most likely at the level of Dvl. These results identify betaarr1
as a regulator of Dvl-dependent LEF transcription and suggest that betaarr1 might
serve as an adapter molecule that can couple Frizzled receptors and perhaps other
GPCRs to these important transcription pathways.
Type
Journal articleSubject
Adaptor Proteins, Signal TransducingAnimals
Arrestins
Cell Line
DNA-Binding Proteins
Dishevelled Proteins
Humans
Lymphoid Enhancer-Binding Factor 1
Mice
Phosphoproteins
Phosphorylation
Protein Binding
Proteins
Transcription Factors
Transcription, Genetic
beta-Arrestins
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https://hdl.handle.net/10161/7809Published Version (Please cite this version)
10.1073/pnas.211572798Publication Info
Chen, W; Hu, LA; Semenov, MV; Yanagawa, S; Kikuchi, A; Lefkowitz, RJ; & Miller, WE (2001). beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through
interaction with phosphorylated dishevelled proteins. Proc Natl Acad Sci U S A, 98(26). pp. 14889-14894. 10.1073/pnas.211572798. Retrieved from https://hdl.handle.net/10161/7809.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Wei Chen
Associate Professor in Medicine
My general area of interest relates to how cancer develops and how to identify cancer
therapeutic agents. In particular I hope to identify molecular signals that underlie
the changes necessary for directing normal tissue to a malignant state in cancer.
Therefore, I have been studying how extracellular signals are deciphered by seven
trans-membrane receptors and their regulatory proteins to control cell proliferation
and differentiation. My major research focuses on studying GPCR, Smoothe
Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is Chancellor’s Distinguished Professor of Medicine and
Professor of Biochemistry and Chemistry at the Duke University Medical Center. He
has bee
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