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.
Dipeptidyl peptidase IV (DPP4/CD26) and seprase/fibroblast activation protein alpha are homologous type II 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 NH(2) 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 mitogenic growth factors, and degradation of denatured collagens (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 II 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.
Ghersi
Giulio
G
Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA.
Zhao
Qiang
Q
Salamone
Monica
M
Yeh
Yunyun
Y
Zucker
Stanley
S
Chen
Wen-Tien
WT
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002465:Cell Movement / Q000502:physiology*; D022081:Cell Surface Extensions / Q000201:enzymology*; D003094:Collagen / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology*; D005109:Extracellular Matrix / Q000378:metabolism*; D005780:Gelatin / Q000378:metabolism; D006801:Humans; D010447:Peptide Hydrolases / Q000096:biosynthesis / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D005780:Gelatin; D003094:Collagen; D010447:Peptide Hydrolases; D018819:Dipeptidyl Peptidase 4; D012697:Serine Endopeptidases; C478147:seprase, human