beta-Arrestin Promotes Wnt-induced Low Density Lipoprotein Receptor-related Protein 6 (Lrp6) Phosphorylation via Increased Membrane Recruitment of Amer1 Protein
| Authors | |
|---|---|
| Year of publication | 2014 |
| Type | Article in Periodical |
| Magazine / Source | Journal of Biological Chemistry |
| MU Faculty or unit | |
| 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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