Heparan Sulfate-modulated, Metalloprotease-mediated Sonic Hedgehog Release from Producing Cells

被引：80

作者：

Dierker, Tabea ^{[1
,2
]}

Dreier, Rita ^{[1
]}

Petersen, Arnd ^{[3
]}

Bordych, Christian ^{[1
]}

Grobe, Kay ^{[1
]}

机构：

[1] Univ Munster, Inst Physiol Chem & Pathobiochem, D-48149 Munster, Germany

[2] Univ Munster, Dept Gen Zool & Genet, D-48149 Munster, Germany

[3] Res Ctr Borstel, Dept Clin Med, D-23845 Borstel, Germany

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2009年 / 284卷 / 12期

关键词：

CHOLESTEROL MODIFICATION; CELLULAR CHOLESTEROL; CRYSTAL-STRUCTURE; TOUT-VELU; ADAM17; MOVEMENT; DOMAIN; ROLES; MICE; INHIBITION;

D O I：

10.1074/jbc.M806838200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The ectodomains of numerous proteins are released from cells by matrix metalloproteases to yield soluble intercellular regulators. A disintegrin and metalloprotease (ADAM) family members have often been found to be the responsible "sheddases," ADAM17/tumor necrosis factor-alpha-converting enzyme being its best characterized member. In this work, we show that ShhNp (lipidated and membrane-tethered Sonic hedgehog) is released from Bosc23 cells by metalloprotease-mediated ectodomain shedding, resulting in a soluble and biologically active morphogen. ShhNp shedding is increased by ADAM17 coexpression and cholesterol depletion of cells with methyl-beta-cyclodextrin and is reduced by metalloprotease inhibitors as well as ADAM17 RNA interference. We also show that the amount of shed ShhNp is modulated by extracellular heparan sulfate (HS) and that ShhNp shedding depends on specific HS sulfations. Based on those data, we suggest new roles for metalloproteases, including but not restricted to ADAM17, and for HS-proteoglycans in Hedgehog signaling.

引用

页码：8013 / 8022

页数：10

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