期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2001
卷号：98
期号：26
页码：14889-14894
DOI：10.1073/pnas.211572798
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 ({beta}arr1) 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-3{beta} (GSK-3{beta}), 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 {beta}arr1, suggesting that regulation of Dvl phosphorylation and subsequent interaction with {beta}arr1 may play a key role in the activation of the LEF transcription pathway. Because coexpression of the Dvl kinases, CK1{varepsilon} and PAR-1, with Dvl synergistically activates LEF reporter gene activity, we reasoned that coexpression of {beta}arr1 with Dvl might also affect LEF-dependent gene activation. Interestingly, whereas {beta}arr1 or Dvl alone leads to low-level stimulation of LEF (2- to 5-fold), coexpression of {beta}arr1 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-3{beta} kinase activity indicate that the step affected by {beta}arr1 is upstream of GSK-3{beta} and most likely at the level of Dvl. These results identify {beta}arr1 as a regulator of Dvl-dependent LEF transcription and suggest that {beta}arr1 might serve as an adapter molecule that can couple Frizzled receptors and perhaps other GPCRs to these important transcription pathways.
