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Cell 2006 Jan 13;1241:147-59. doi: 10.1016/j.cell.2005.12.018.
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Embryonic dorsal-ventral signaling: secreted frizzled-related proteins as inhibitors of tolloid proteinases.

Lee HX , Ambrosio AL , Reversade B , De Robertis EM .

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.

PubMed ID: 16413488
PMC ID: PMC2486255
Article link: Cell
Grant support: [+]

Species referenced: Xenopus
Genes referenced: bmp1 bmp4 chrd egr2 otx2 rax sfrp2 smad1 sox2 szl tll1 tll2 twsg1
Morpholinos: bmp2 MO1 bmp4 MO1 bmp7.2 MO1 chrd.1 MO1 chrd.1 MO2 szl MO1 wnt8a MO3

Article Images: [+] show captions
References [+] :
Baker, Metalloproteinase inhibitors: biological actions and therapeutic opportunities. 2002, Pubmed