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. 2017 Oct 9;43(1):71-82.e6.
doi: 10.1016/j.devcel.2017.09.011.

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

Nadine Kirsch  1 , Ling-Shih Chang  1 , Stefan Koch  1 , Andrey Glinka  1 , Christine Dolde  1 , Gabriele Colozza  2 , Maria D J Benitez  2 , Edward M De Robertis  2 , Christof Niehrs  3
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Free article

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

Nadine Kirsch et al. Dev Cell. .
Free article

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.

Keywords: LRP6; Wnt/β-catenin signaling; angiopoietin-like 4; syndecan.

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