Embryonic dorsal-ventral signaling: Secreted Frizzled-related proteins as inhibitors of tolloid proteinases
Embryonic dorsal-ventral signaling: Secreted Frizzled-related proteins as inhibitors of tolloid proteinases
复制标题
DOI：
10.1016/j.cell.2005.12.018
复制
发表时间：
2006-01-13
期刊：
影响因子：
64.5
通讯作者：
De Robertis, EM
中科院分区：
文献类型：
--
作者：
Lee, HX;Ambrosio, AL;De Robertis, EM
在这里，我们报道了分泌型卷曲相关蛋白 (sFRP) Sizzled/Ogon 作为细胞外蛋白水解反应抑制剂的意外作用，该反应控制非洲爪蟾原肠胚形成过程中的 BMP 信号传导。显微注射实验表明，Sizzled 的 Frizzled 结构域通过以下分子途径调节 Xolloid 相关 (Xlr)（一种降解 Chordin 的金属蛋白酶）的活性：Szl Xlr I Chd d BMP -> P-Smad1 -> Szl。在生化测定中，Xlr 蛋白酶与其内源性底物 Chordin 及其竞争性抑制剂 Sizzled 具有相似的亲和力，后者对酶消化具有抵抗力。原肠胚中Sizzled和Chordin的细胞外水平和酶反应常数均在10(-8)M范围内，这与调节背腹模式的生理作用一致。 Sizzled 也是 BMP1 的天然抑制剂，BMP1 是一种具有医学意义的 Tolloid 金属蛋白酶。此外，小鼠 sFRP2 抑制 Xlr，表明这种分子机制具有更广泛的作用。
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 I Chd d 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.