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Dev Cell January 1, 2017; 43 (1): 71-82.e6.

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

Kirsch N , Chang LS , Koch S , Glinka A , Dolde C , Colozza G , Benitez MDJ , De Robertis EM , Niehrs C .

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.

PubMed ID: 29017031
Article link: Dev Cell
Grant support: Howard Hughes Medical Institute

Genes referenced: angptl4 axin2 cer1 ctnnb1 dkk1 dkk2 dkk3 dvl1 en2 fzd8 gsc lgr4 lgr5 lrp5 lrp6 myf5 nodal3.1 nog not rspo3 sdc1 sdc2 sdc3 sdc4 wnt1 wnt3a

Antibodies referenced: Ctnnb1 Ab8 Lrp5 Ab1 Lrp6 Ab1 Lrp6 Ab2 Mapk1 Ab3 Tuba4a Ab3
Morpholinos referenced: angptl4 MO1 angptl4 MO2 lrp6 MO1 sdc4 MO1 sdc4 MO2
Disease Ontology references: coronary artery disease

External Resources: GO Terms referenced: lipid metabolic process [+]

Article Images: [+] show captions

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