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

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

doi:10.1016/j.cell.2005.12.018

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

Neurobiology

Research output: Contribution to journal › Article › peer-review

195 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 language	English (US)
Pages (from-to)	147-159
Number of pages	13
Journal	Cell
Volume	124
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2005.12.018
State	Published - Jan 13 2006

Funding

We thank Drs. W. Wang and R. Lehrer for generous assistance with BIAcore analysis, Drs. L. Dale, C. Heldin, J.C. Hsieh, J. Nathans, and J. Larrain for reagents, and members of our laboratory for comments on the manuscript. This work was supported by the NIH (R37 HD21502-19). A.L.A. was supported by a postdoctoral fellowship of the Jonsson Cancer Center Foundation/UCLA. E.M.D.R. is an Investigator of the Howard Hughes Medical Institute.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2005.12.018

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title = "Embryonic dorsal-ventral signaling: Secreted Frizzled-related proteins as inhibitors of tolloid proteinases",

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.",

author = "Hojoon Lee and Ambrosio, {Andrea L.} and Bruno Reversade and {De Robertis}, {E. M.}",

note = "Funding Information: We thank Drs. W. Wang and R. Lehrer for generous assistance with BIAcore analysis, Drs. L. Dale, C. Heldin, J.C. Hsieh, J. Nathans, and J. Larrain for reagents, and members of our laboratory for comments on the manuscript. This work was supported by the NIH (R37 HD21502-19). A.L.A. was supported by a postdoctoral fellowship of the Jonsson Cancer Center Foundation/UCLA. E.M.D.R. is an Investigator of the Howard Hughes Medical Institute. ",

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AU - De Robertis, E. M.

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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.

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.

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

Abstract

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