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J. Biol. Chem., Vol. 275, Issue 48, 37638-37644, December 1, 2000
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From the Cultured fibroblasts secrete an 88-kDa serine
protease that cleaves insulin-like growth factor binding protein-5
(IGFBP-5). Because IGFBP-5 has been shown to regulate IGF-I actions,
understanding the chemical identity and regulation of this protease is
important for understanding how IGF-I stimulates anabolic functions.
The protease was purified from human fibroblast-conditioned medium by
hydrophobic interaction, lectin affinity, and heparin Sepharose affinity chromatography followed by SDS-polyacrylamide gel
electrophoresis. An 88-kDa band was excised and digested with
lysyl-endopeptidase. Sequencing of the high pressure liquid
chromatography-purified peptides yielded the complement components C1r
and C1s. To confirm that C1r/C1s accounted for the proteolytic activity
in the medium, immunoaffinity chromatography was performed. Most of the
protease activity adhered to the column, and the eluant was fully
active in cleaving IGFBP-5. SDS-polyacrylamide gel electrophoresis with silver staining showed two bands, and IGFBP-5 zymography showed a
single 88-kDa band. Amino acid sequencing confirmed that the 88-kDa
band contained only C1r and C1s. C1r in the fibroblast medium underwent
autoactivation, and the activated form cleaved C1s. C1s purified from
the conditioned medium cleaved C4, a naturally occurring
substrate. The purified protease cleaved IGFBP-5 but had no activity
against IGFBP-1 through -4. C1 inhibitor, a protein known to inhibit
activated C1s, was shown to inhibit the cleavage of IGFBP-5 by the
protease in the conditioned medium. In summary, human fibroblasts
secrete C1r and C1s that actively cleave IGFBP-5. The findings define a
mechanism for cleaving IGFBP-5 in the culture medium, thus allowing
release of IGF-I to cell surface receptors.
The Complement Component C1s Is the Protease That Accounts
for Cleavage of Insulin-like Growth Factor-binding Protein-5 in
Fibroblast Medium*
,,,¶
Department of Medicine, University of North Carolina
School of Medicine, Chapel Hill, North Carolina 27599-7170 and the
§ Department of Protein Chemistry, Monsanto, Inc., Chesterfield,
Missouri 63198
*
This work was supported by Grant AGO23331 from the National
Institutes of Health.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.
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