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J. Biol. Chem., Vol. 277, Issue 13, 11034-11041, March 29, 2002
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From the Proteolysis of the hyalectans (aggrecan,
versican, brevican) in vivo appears to result from the
activity of ADAMTS4 (aggrecanase-1, herein referred to as an
hyalectanase). To examine the mode of activation of ADAMTS4, a human
chondrosarcoma cell line, JJ012, has been stably transfected with the
full-length c-DNA for human ADAMTS4. The cells synthesized a high
molecular weight form of the enzyme (p100), which in serum-free culture
was processed to three truncated forms, p75, p60, and p50. Treatment of
the p100 form with recombinant furin indicated that the p75 form is
generated by the removal of the prodomain by a furin-like activity.
Analysis with domain-specific antisera showed that the p60 and p50
forms are generated by C-terminal truncation of the p75 form. The
appearance of the p60 and p50 forms in culture medium was prevented by
inclusion of a furin inhibitor, inhibitors of
glycosylphosphatidylinositol synthesis, glucosamine, a
hydroxamate-based matrix metalloproteinase (MMP) inhibitor, and TIMP-1,
but not by AEBSF (4-(2-aminoethyl)benzenesulfonyl fluoride) or E64.
Only medium samples containing the p60/p50 forms exhibited aggrecanase
activity, and isolation of the p75, p60, and p50 forms by preparative
SDS-PAGE showed that only p60 and p50 were active in aggrecanase and
versicanase assays. Pig synovium and human cartilages also
contained ADAMTS4 in the p75, p60, and p50 forms. We suggest that
in vivo production of proteolytically active ADAMTS4
requires not only removal of the prodomain by a furin-like activity but
also MMP-mediated removal of a portion of the C-terminal spacer domain.
Activation of the Proteolytic Activity of ADAMTS4 (Aggrecanase-1)
by C-terminal Truncation*
,,,,§¶
Center For Research in Skeletal Development
and Paediatric Orthopaedics, Shriners Hospital for Children and
the § Department of Pharmacology and Therapeutics,
University of South Florida, Tampa, Florida 33612
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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