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

Publication date: 9 October 2017
Source:Developmental Cell, Volume 43, Issue 1
Author(s): Nadine Kirsch, Ling-Shih Chang, Stefan Koch, Andrey Glinka, Christine Dolde, Gabriele Colozza, Maria D.J. Benitez, Edward M. De Robertis, Christof Niehrs
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.

Teaser

Kirsch et al. identify ANGPTL4 as an antagonist of the Wnt/β-catenin signaling pathway. ANGPTL4 binds syndecans to induce internalization and lysosomal degradation of the Wnt co-receptor LRP6, thereby inhibiting Wnt/β-catenin signaling. In Xenopus embryos, angptl4 is expressed in the Spemann organizer and antagonizes Wnt to promote notochord development.


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