TY - JOUR
T1 - Embryonic dorsal-ventral signaling: Secreted Frizzled-related proteins as inhibitors of tolloid proteinases
AU - Lee, Hojoon X.
AU - Ambrosio, Andrea L.
AU - Reversade, Bruno
AU - De Robertis, E. M.
N1 - Generated from Scopus record by KAUST IRTS on 2023-02-15
PY - 2006/1/13
Y1 - 2006/1/13
N2 - 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. ©2006 Elsevier Inc.
AB - 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. ©2006 Elsevier Inc.
UR - https://linkinghub.elsevier.com/retrieve/pii/S0092867405014133
UR - http://www.scopus.com/inward/record.url?scp=30344486313&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2005.12.018
DO - 10.1016/j.cell.2005.12.018
M3 - Article
SN - 0092-8674
VL - 124
SP - 147
EP - 159
JO - Cell
JF - Cell
IS - 1
ER -