SOST Is a Ligand for LRP5/LRP6 and a Wnt Signaling Inhibitor*

By M. Semënov, K. Tamai, Xi He. Journal of Biological Chemistry, 2005

801 citations recorded by the source corpus.

Sclerosteosis is an autosomal recessive disease that is characterized by overgrowth of bone tissue and is linked to mutations in the gene encoding the secreted protein SOST. Sclerosteosis shares remarkable similarities with “high bone mass” diseases caused by “gain-of-function” mutations in the LRP5 gene, which encodes a coreceptor for Wnt signaling proteins. We show here that SOST antagonizes Wnt signaling in Xenopus embryos and mammalian cells by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. Our findings suggest that SOST is an antagonist for Wnt signaling and that the loss of SOST function likely leads to the hyperactivation of Wnt signaling that underlies bone overgrowth seen in sclerosteosis patients.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/57c9137f293a0063cd0ac68208a81a7a49875a9f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Hans Clevers
2. R. Nusse
3. Christof Niehrs
4. Fanxin Long
5. Pengfei Lu

In Molecular Biology

1. Hans Clevers
2. R. Nusse
3. Christof Niehrs
4. Cristina Cruciat
5. Fanxin Long
6. Elaine Fuchs
7. C. Blanpain
8. Xi He

Citations in the corpus

• Wnt/β-catenin signaling and disease. (2012, positive): “Like DKK1, SOST can disrupt Wntinduced Fz-LRP6 complexes in vitro (Semënov et al., 2005).”
• Building strong bones: molecular regulation of the osteoblast lineage (2011, background): “Sclerostin seems to function mainly by inhibiting WNT signalling in osteoblast lineage cells, which promotes osteoblast differentiation (see below), but inhibition of bone morphogenetic protein (BMP) signalling has also been suggeste”
• Secreted and transmembrane wnt inhibitors and activators. (2013, background): “SOSTantagonizes Wnt signaling by binding to the first two YWTD–EGF repeat domains of LRP5 and LRP6 (Li et al. 2005b; Semenov et al. 2005).”
• Wnt/beta-catenin signaling in development and disease. (2006, neutral): “It remains presently debated whether Wnt controls GSK3-mediated phosphorylation of LRP5/6 (Zeng et al., 2005) or whether CK1γ is the kinase regulated by Wnt (Davidson et al., 2005).”