Embryonic dorsal-ventral signaling: secreted frizzled-related proteins as inhibitors of tolloid proteinases.
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.
Lee
Hojoon X
HX
Howard Hughes Medical Institute, Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA.
Ambrosio
Andrea L
AL
Reversade
Bruno
B
De Robertis
E M
EM
D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D005775:Gastrula / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship; D055394:Tolloid-Like Metalloproteinases; D014981:Xenopus / Q000196:embryology / Q000378:metabolism; D029867:Xenopus Proteins / Q000378:metabolism / Q000502:physiology*; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008666:Metalloendopeptidases; D011480:Protease Inhibitors; D055394:Tolloid-Like Metalloproteinases; D029867:Xenopus Proteins; D000099274:Frizzled-Related Proteins; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C109976:szl protein, Xenopus; C054234:chordin; C575919:tll1 protein, Xenopus; C525707:Bmp1 protein, mouse