Abstract
During tumor invasion, tumor cells degrade the extracellular matrix. Basement membrane degradation is responsible for the production of peptides with anti-tumor properties. Type XIX collagen is associated with basement membranes in vascular, neuronal, mesenchymal and epithelial tissues. Previously, we demonstrated that the non-collagenous NC1, C-terminal, domain of collagen XIX [NC1(XIX)] inhibits the migration capacities of tumor cells and exerts a strong inhibition of tumor growth. Here, we demonstrate that plasmin, one of the most important enzyme involved in tumor invasion, was able to release a fragment of NC1(XIX), which retained the anti-tumor activity. Molecular modeling studies showed that NC1(XIX) and the anti-tumor fragment released by plasmin (F4) adopted locally the same type I β-turn conformation. This suggests that the anti-tumor effect is conformation-dependent. This study demonstrates that collagen XIX is a novel proteolytic substrate for plasmin. Such release may constitute a defense of the organism against tumor invasion.
Highlights
IntroductionThe basement membrane is a complex structure mainly composed of laminins, nidogens, heparan sulfate proteoglycans (perlecan and/or agrin), and type IV collagen
The basement membrane is a complex structure mainly composed of laminins, nidogens, heparan sulfate proteoglycans, and type IV collagen
To evaluate whether plasmin could cleave the C-terminal domain of type XIX collagen, we used a synthetic peptide (P36) composed of the last 36 residues of the human α1(XIX) chain, homologous to that previously described by Boudko et al [29]
Summary
The basement membrane is a complex structure mainly composed of laminins, nidogens, heparan sulfate proteoglycans (perlecan and/or agrin), and type IV collagen. Associations between basement membrane and minor collagens such as type XVIII, XV or type XIX were reported and named basement membrane zone [1, 2]. These collagenous components associated with the basement membrane represent a dynamic interface between this structure and the stroma. Basement membrane has long been described as a simple architectural cell support. It exerts many important biological functions and plays key role in many physiological and pathological situations [3, 4]. It was previously shown that MMP-9 might release tumstatin from type IV collagen in vivo [7]
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