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. 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.

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

Colozza G.
Methodology
;
2017-01-01

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. 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.
2017
Kirsch, N.; Chang, L. -S.; Koch, S.; Glinka, A.; Dolde, C.; Colozza, G.; Benitez, M. D. J.; De Robertis, E. M.; Niehrs, C.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1274251
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