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Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover.

  • Author(s): Kirsch, Nadine;
  • Chang, Ling-Shih;
  • Koch, Stefan;
  • Glinka, Andrey;
  • Dolde, Christine;
  • Colozza, Gabriele;
  • Benitez, Maria DJ;
  • De Robertis, Edward M;
  • Niehrs, Christof
  • et al.
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.

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