Specific processing of tenascin-C by the metalloprotease meprinbeta neutralizes its inhibition of cell spreading

Ambort, Daniel; Brellier, Florence; Becker-Pauly, Christoph; Stöcker, Walter; Andrejevic-Blant, Snezana; Chiquet, Matthias; Sterchi, Erwin E (2010). Specific processing of tenascin-C by the metalloprotease meprinbeta neutralizes its inhibition of cell spreading. Matrix biology, 29(1), pp. 31-42. Amsterdam: Elsevier 10.1016/j.matbio.2009.08.007

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The metalloprotease meprin has been implicated in tissue remodelling due to its capability to degrade extracellular matrix components. Here, we investigated the susceptibility of tenascin-C to cleavage by meprinbeta and the functional properties of its proteolytic fragments. A set of monoclonal antibodies against chicken and human tenascin-C allowed the mapping of proteolytic fragments generated by meprinbeta. In chicken tenascin-C, meprinbeta processed all three major splicing variants by removal of 10kDa N-terminal and 38kDa C-terminal peptides, leaving a large central part of subunits intact. A similar cleavage pattern was found for large human tenascin-C variant where two N-terminal peptides (10 or 15kDa) and two C-terminal fragments (40 and 55kDa) were removed from the intact subunit. N-terminal sequencing revealed the exact amino acid positions of cleavage sites. In both chicken and human tenascin-C N-terminal cleavages occurred just before and/or after the heptad repeats involved in subunit oligomerization. In the human protein, an additional cleavage site was identified in the alternative fibronectin type III repeat D. Whereas all these sites are known to be attacked by several other proteases, a unique cleavage by meprinbeta was located to the 7th constant fibronectin type III repeat in both chicken and human tenascin-C, thereby removing the C-terminal domain involved in its anti-adhesive activity. In cell adhesion assays meprinbeta-digested human tenascin-C was not able to interfere with fibronectin-mediated cell spreading, confirming cleavage in the anti-adhesive domain. Whereas the expression of meprinbeta and tenascin-C does not overlap in normal colon tissue, inflamed lesions of the mucosa from patients with Crohn's disease exhibited many meprinbeta-positive leukocytes in regions where tenascin-C was strongly induced. Our data indicate that, at least under pathological conditions, meprinbeta might attack specific functional sites in tenascin-C that are important for its oligomerization and anti-adhesive activity.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > School of Dental Medicine > Department of Orthodontics 04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
UniBE Contributor:	Chiquet, Matthias, Sterchi, Erwin-Ernst
ISSN:	0945-053X
Publisher:	Elsevier
Language:	English
Submitter:	Eveline Carmen Schuler
Date Deposited:	04 Oct 2013 14:07
Last Modified:	05 Dec 2022 14:00
Publisher DOI:	10.1016/j.matbio.2009.08.007
PubMed ID:	19748582
Web of Science ID:	000274530200005
URI:	https://boris.unibe.ch/id/eprint/125 (FactScience: 196266)