Heparan sulfate-modulated, metalloprotease-mediated sonic hedgehog release from producing cells.
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.
Dierker
Tabea
T
Institute for Physiological Chemistry and Pathobiochemistry, Westfälische Wilhelms-Univertät Münster, Münster, Germany.
Dreier
Rita
R
Petersen
Arnd
A
Bordych
Christian
C
Grobe
Kay
K
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D053823:Hedgehog Proteins / Q000378:metabolism*; D006497:Heparan Sulfate / Q000494:pharmacology*; D051379:Mice; D047392:beta-Cyclodextrins / Q000494:pharmacology
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D002784:Cholesterol; D053823:Hedgehog Proteins; D006497:Heparan Sulfate; D047392:beta-Cyclodextrins; C465570:Shh protein, mouse; C108732:methyl-beta-cyclodextrin; C000606463:Adam17 protein, mouse