beta-Arrestin Promotes Wnt-induced Low Density Lipoprotein Receptor-related Protein 6 (Lrp6) Phosphorylation via Increased Membrane Recruitment of Amer1 Protein

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Authors

KŘÍŽ Vítězslav POSPÍCHALOVÁ Vendula MAŠEK Jan KILANDER Michaela Brita Christina SLAVIK Josef TANNEBERGER Kristina SCHULTE Gunnar MCHALA Miroslav KOZUBÍK Alois BEHRENS Jurgen BRYJA Vítězslav

Year of publication 2014
Type Article in Periodical
Magazine / Source Journal of Biological Chemistry
MU Faculty or unit

Faculty of Science

Citation
Web https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887180/
Doi http://dx.doi.org/10.1074/jbc.M113.498444
Field Genetics and molecular biology
Keywords CONVERGENT EXTENSION MOVEMENTS; SIGNALING PATHWAYS; IN-VIVO; CATENIN; ACTIVATION; BETA-ARRESTIN-2; DVL; APC; ENDOCYTOSIS; MECHANISM
Description beta-Arrestin is a scaffold protein that regulates signal transduction by seven transmembrane-spanning receptors. Among other functions it is also critically required for Wnt/beta-catenin signal transduction. In the present study we provide for the first time a mechanistic basis for the beta-arrestin function in Wnt/beta-catenin signaling. We demonstrate that beta-arrestin is required for efficient Wnt3a-induced Lrp6 phosphorylation, a key event in downstream signaling. beta-Arrestin regulates Lrp6 phosphorylation via a novel interaction with phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P-2)-binding protein Amer1/WTX/Fam123b. Amer1 has been shown very recently to bridge Wnt-induced and Dishevelled-associated PtdIns(4,5)P-2 production to the phosphorylation of Lrp6. Using fluorescence recovery after photobleaching we show here that beta-arrestin is required for the Wnt3a-induced Amer1 membrane dynamics and downstream signaling. Finally, we show that beta-arrestin interacts with PtdIns kinases PI4KII alpha and PIP5KI beta. Importantly, cells lacking beta-arrestin showed higher steady-state levels of the relevant PtdInsP and were unable to increase levels of these PtdInsP in response to Wnt3a. In summary, our data show that beta-arrestins regulate Wnt3a-induced Lrp6 phosphorylation by the regulation of the membrane dynamics of Amer1. We propose that beta-arrestins via their scaffolding function facilitate Amer1 interaction with PtdIns(4,5)P-2, which is produced locally upon Wnt3a stimulation by beta-arrestin- and Dishevelled-associated kinases.
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