1. Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover.
- Author
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Kirsch N, Chang LS, Koch S, Glinka A, Dolde C, Colozza G, Benitez MDJ, De Robertis EM, and Niehrs C
- Subjects
- Angiopoietin-Like Protein 4, Angiopoietins genetics, Animals, Humans, Low Density Lipoprotein Receptor-Related Protein-6 genetics, Phosphorylation, Signal Transduction physiology, Wnt3A Protein metabolism, Xenopus, Xenopus Proteins genetics, Angiopoietins metabolism, Endocytosis physiology, Low Density Lipoprotein Receptor-Related Protein-6 metabolism, Receptors, LDL metabolism, Wnt Signaling Pathway physiology, Xenopus Proteins metabolism, beta Catenin metabolism
- Abstract
Angiopoietin-like 4 (ANGPTL4) is a secreted signaling protein that is implicated in cardiovascular disease, metabolic disorder, and cancer. Outside of its role in lipid metabolism, ANGPTL4 signaling remains poorly understood. Here, we identify ANGPTL4 as a Wnt signaling antagonist that binds to syndecans and forms a ternary complex with the Wnt co-receptor Lipoprotein receptor-related protein 6 (LRP6). This protein complex is internalized via clathrin-mediated endocytosis and degraded in lysosomes, leading to attenuation of Wnt/β-catenin signaling. Angptl4 is expressed in the Spemann organizer of Xenopus embryos and acts as a Wnt antagonist to promote notochord formation and prevent muscle differentiation. This unexpected function of ANGPTL4 invites re-interpretation of its diverse physiological effects in light of Wnt signaling and may open therapeutic avenues for human disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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