The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices
The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices
复制标题
DOI：
10.1158/0008-5472.can-05-1245
复制
发表时间：
2006-05-01
期刊：
影响因子：
11.2
通讯作者：
Chen, Wen-Tien
中科院分区：
文献类型：
--
作者：
Ghersi, Giulio;Zhao, Qiang;Chen, Wen-Tien
二肽基肽酶IV （DPP4/CD26）和sepprase /成纤维细胞活化蛋白α是同源的11型跨膜二聚体糖蛋白，具有独特的脯氨酸肽酶活性。人类DPP4在上皮细胞和内皮细胞中普遍表达，并在循环中切割多种生理上重要的肽的NH2端倒数第二个位置的脯氨酸键中发挥多种功能。最近的研究表明，DPP4与某些趋化因子和致畸生长因子的下调以及变性胶原（明胶）的降解之间存在联系，表明DPP4在细胞侵袭表型中起作用。在这里，我们发现在人内皮细胞中存在一种由DPP4和seprase组成的新型蛋白酶复合物，该复合物在体外被激活以迁移和侵入细胞外基质。DPP4和seprase与三种主要的蛋白酶系统（基质金属蛋白酶、纤溶酶原激活剂和11型跨膜丝氨酸蛋白酶）在细胞表面共表达，并在侵殖样突起处形成复合体。在浸润性乳腺导管癌中，两种蛋白酶均在毛细血管内皮细胞而非大血管中共定位。重要的是，针对DPP4明胶结合域的单克隆抗体阻断了内皮细胞在主要金属和丝氨酸蛋白酶系统存在下的局部明胶降解，这些系统修饰了细胞周围胶原基质和随后的细胞迁移和侵袭。因此，我们已经确定了一种涉及DPP4-seprase复合物的DPP4明胶结合域的新机制，该机制促进了细胞外基质的局部降解和内皮细胞侵入胶原基质。
Dipeptidyl peptidase IV (DPP4/CD26) and seprase/fibroblast activation protein alpha are homologous type 11 transmembrane, homodimeric glycoproteins that exhibit unique prolyl peptidase activities. Human DPP4 is ubiquitously expressed in epithelial and endothelial cells and serves multiple functions in cleaving the penultimate positioned prolyl bonds at the NH2 terminus of a variety of physiologically important peptides in the circulation. Recent studies showed a linkage between DPP4 and down-regulation of certain chemokines and mi- togenic growth factors, and degradation of denatured colla- gens (gelatin), suggesting a role of DPP4 in the cell invasive phenotype. Here, we found the existence of a novel protease complex consisting of DPP4 and seprase in human endothelial cells that were activated to migrate and invade in the extracellular matrix in vitro. DPP4 and seprase were coexpressed with the three major protease systems (matrix metalloproteinase, plasminogen activator, and type 11 transmembrane serine protease) at the cell surface and organize as a complex at invadopodia-like protrusions. Both proteases were colocalized at the endothelial cells of capillaries, but not large blood vessels, in invasive breast ductal carcinoma in vivo. Importantly, monoclonal antibodies against the gelatin-binding domain of DPP4 blocked the local gelatin degradation by endothelial cells in the presence of the major metallo- and serine protease systems that modified pericellular collagenous matrices and subsequent cell migration and invasion. Thus, we have identified a novel mechanism involving the DPP4 gelatin-binding domain of the DPP4-seprase complex that facilitates the local degradation of the extracellular matrix and the invasion of the endothelial cells into collagenous matrices.