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Dev Cell 2017 Oct 09;431:71-82.e6. doi: 10.1016/j.devcel.2017.09.011.
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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: [+]

Species referenced: Xenopus
Genes referenced: angptl4 axin2 cer1 chrd.1 cltc ctnnb1 dkk1 dkk2 dkk3 dvl1 en2 fn1 fzd8 gsc kit lgr4 lgr5 lrp5 lrp6 mapk1 myc myf5 nodal3.1 nog not rnf2 rspo3 sdc1 sdc2 sdc3 sdc4 wnt1 wnt3a wnt8a
GO keywords: lipid metabolic process [+]
Antibodies: Ctnnb1 Ab8 Lrp5 Ab1 Lrp6 Ab1 Lrp6 Ab2 Mapk1 Ab3 Tuba4a Ab3
Morpholinos: angptl4 MO1 angptl4 MO2 lrp6 MO1 sdc4 MO1 sdc4 MO2

Disease Ontology terms: coronary artery disease
Phenotypes: Xla Wt + angptl4 (Fig 2. D) [+]

Article Images: [+] show captions