Kallikrein-related Peptidase 12 Hydrolyzes Matricellular Proteins of the CCN Family and Modifies Interactions of CCN1 and CCN5 with Growth Factors

Kallikrein-related peptidases (KLKs) are an emerging group of secreted serine proteases involved in several physiological and pathological processes. We used a degradomic approach to identify potential substrates of KLK12. MDA-MB-231 cells were treated either with KLK12 or vehicle control, and the p...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 286; no. 29; pp. 25505 - 25518
Main Authors:	Guillon-Munos, Audrey, Oikonomopoulou, Katerina, Michel, Noémie, Smith, Chistopher R., Petit-Courty, Agnès, Canepa, Sylvie, Reverdiau, Pascale, Heuzé-Vourc'h, Nathalie, Diamandis, Eleftherios P., Courty, Yves
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 22-07-2011 American Society for Biochemistry and Molecular Biology
Subjects:	Angiogenesis Biochemistry Biochemistry, Molecular Biology CCN Intercellular Signaling Proteins CCN Protein Cell Biology Cell Line, Tumor Cysteine-Rich Protein 61 - genetics Cysteine-Rich Protein 61 - metabolism Extracellular Matrix Proteins Gene Expression Regulation, Neoplastic Growth Factors Homeostasis - drug effects Humans Hydrolysis Intercellular Signaling Peptides and Proteins - genetics Intercellular Signaling Peptides and Proteins - metabolism Kallikrein-related Peptidase Kallikreins - genetics Kallikreins - metabolism Kallikreins - pharmacology Life Sciences Ligand-binding Protein Lung - cytology Lung - metabolism Lung - pathology Lung Neoplasms - genetics Protein Binding - drug effects Protein Transport - drug effects Proteolysis Proteomics Repressor Proteins Reproducibility of Results Serine Protease Transcription Factors - genetics Transcription Factors - metabolism Transforming Growth Factor Beta (TGF-beta) Ligand-binding Protein CCN Protein Angiogenesis Serine Protease Growth Factors Extracellular Matrix Proteins Proteolysis Kallikrein-related Peptidase Transforming Growth Factor Beta (TGF-beta) kallicréine protéine ccn cancer cellulle endothéliale
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Summary:	Kallikrein-related peptidases (KLKs) are an emerging group of secreted serine proteases involved in several physiological and pathological processes. We used a degradomic approach to identify potential substrates of KLK12. MDA-MB-231 cells were treated either with KLK12 or vehicle control, and the proteome of the overlying medium was analyzed by mass spectrometry. CCN1 (cyr61, ctgf, nov) was among the proteins released by the KLK12-treated cells, suggesting that KLK12 might be responsible for the shedding of this protein from the cell surface. Fragmentation of CCN1 by KLK12 was further confirmed in vitro, and the main cleavage site was localized in the hinge region between the first and second half of the recombinant protein. KLK12 can target all six members of the CCN family at different proteolytic sites. Limited proteolysis of CCNs (cyr61, ctgf, nov) was also observed in the presence of other members of the KLK family, such as KLK1, KLK5, and KLK14, whereas KLK6, KLK11, and KLK13 were unable to fragment CCNs. Because KLK12 seems to have a role in angiogenesis, we investigated the relations between KLK12, CCNs, and several factors known to be involved in angiogenesis. Solid phase binding assays showed that fragmentation of CCN1 or CCN5 by KLK12 prevents VEGF165 binding, whereas it also triggers the release of intact VEGF and BMP2 from the CCN complexes. The KLK12-mediated release of TGF-β1 and FGF-2, either as intact or truncated forms, was found to be concentration-dependent. These findings suggest that KLK12 may indirectly regulate the bioavailability and activity of several growth factors through processing of their CCN binding partners.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M110.213231