β-Arrestin1 Modulates Lymphoid Enhancer Factor Transcriptional Activity through Interaction with Phosphorylated Dishevelled Proteins

One aspect of the function of the β-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 β-arrestin1 (βarr1) 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-3β (GSK-3β), stabilization of β-catenin, and activation of the lymphoid enhancer factor (LEF) transcription factor. We find that phosphorylation of Dvl strongly enhances its interaction with βarr1, suggesting that regulation of Dvl phosphorylation and subsequent interaction with βarr1 may play a key role in the activation of the LEF transcription pathway. Because coexpression of the Dvl kinases, CK1ε and PAR-1, with Dvl synergistically activates LEF reporter gene activity, we reasoned that coexpression of βarr1 with Dvl might also affect LEF-dependent gene activation. Interestingly, whereas βarr1 or Dvl alone leads to low-level stimulation of LEF (2- to 5-fold), coexpression of βarr1 with either Dvl1 or Dvl2 leads to a synergistic activation of LEF (up to 16-fold). Additional experiments with LiCI as an inhibitor of GSK-3β kinase activity indicate that the step affected by βarr1 is upstream of GSK-3β and most likely at the level of Dvl. These results identify βarr1 as a regulator of Dvl-dependent LEF transcription and suggest that βarr1 might serve as an adapter molecule that can couple Frizzled receptors and perhaps other GPCRs to these important transcription pathways.