Regulation of fibroblast migration on collagenous matrix by a cell surface peptidase complex.
The invasion of migratory cells through connective tissues involves metallo- and serine types of cell surface proteases. We show that formation of a novel protease complex, consisting of the membrane-bound prolyl peptidases seprase and dipeptidyl peptidase IV (DPPIV), at invadopodia of migratory fibroblasts is a prerequisite for cell invasion and migration on a collagenous matrix. Seprase and DPPIV form a complex on the cell surface that elicits both gelatin binding and gelatinase activities localized at invadopodia of cells migrating on collagenous fibers. The protease complex participates in the binding to gelatin and localized gelatin degradation, cellular migration, and monolayer wound closure. Serine protease inhibitors can block the gelatinase activity and the localized gelatin degradation by cells. Antibodies to the gelatin-binding domain of DPPIV reduce the cellular abilities of the proteases to degrade gelatin but do not affect cellular adhesion or spreading on type I collagen. Furthermore, expression of the seprase-DPPIV complex is restricted to migratory cells involved in wound closure in vitro and in connective tissue cells during closure of gingival wounds but not in differentiated tissue cells. Thus, we have identified cell surface proteolytic activities, which are non-metalloproteases, seprase and DPPIV, that are responsible for the tissue-invasive phenotype.
Ghersi
Giulio
G
Department of Medicine/Medical Oncology, State University of New York, Stony Brook, New York 11794-8154, USA.
Dong
Huan
H
Goldstein
Leslie A
LA
Yeh
Yunyun
Y
Hakkinen
Lari
L
Larjava
Hannu S
HS
Chen
Wen-Tien
WT
D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion; D002454:Cell Differentiation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002850:Chromatography, Gel; D003094:Collagen / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases; D005347:Fibroblasts / Q000378:metabolism*; D005780:Gelatin / Q000378:metabolism / Q000494:pharmacology; D018093:Gelatinases / Q000737:chemistry / Q000378:metabolism*; D005881:Gingiva / Q000473:pathology; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D010447:Peptide Hydrolases / Q000737:chemistry*; D010641:Phenotype; D011485:Protein Binding; D051381:Rats; D012697:Serine Endopeptidases; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D000099167:Fibroblast Activation Protein Alpha
D003094:Collagen; D018819:Dipeptidyl Peptidase 4; D010450:Endopeptidases; D005780:Gelatin; D018093:Gelatinases; D008024:Ligands; D008565:Membrane Proteins; D010447:Peptide Hydrolases; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha