Embryonic dorsal-ventral signaling: Secreted Frizzled-related proteins as inhibitors of tolloid proteinases

Hojoon Lee, Andrea L. Ambrosio, Bruno Reversade, E. M. De Robertis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

Abstract

Here we report an unexpected role for the secreted Frizzled-related protein (sFRP) Sizzled/Ogon as an inhibitor of the extracellular proteolytic reaction that controls BMP signaling during Xenopus gastrulation. Microinjection experiments suggest that the Frizzled domain of Sizzled regulates the activity of Xolloid-related (Xlr), a metalloproteinase that degrades Chordin, through the following molecular pathway: Szl ⊣ Xlr ⊣ Chd ⊣ BMP → P-Smad1 → Szl. In biochemical assays, the Xlr proteinase has similar affinities for its endogenous substrate Chordin and for its competitive inhibitor Sizzled, which is resistant to enzyme digestion. Extracellular levels of Sizzled and Chordin in the gastrula embryo and enzyme reaction constants were all in the 10-8 M range, consistent with a physiological role in the regulation of dorsal-ventral patterning. Sizzled is also a natural inhibitor of BMP1, a Tolloid metalloproteinase of medical interest. Furthermore, mouse sFRP2 inhibited Xlr, suggesting a wider role for this molecular mechanism.

Original languageEnglish (US)
Pages (from-to)147-159
Number of pages13
JournalCell
Volume124
Issue number1
DOIs
StatePublished - Jan 13 2006

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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