title: Discoidin domain receptor 2 mediates collagen-induced activation of membrane-type 1 matrix metalloproteinase in human fibroblasts.
abstract: Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a membrane-bound MMP that is highly expressed in cells with invading capacity, including fibroblasts and invasive cancer cells. However, pathways of MT1-MMP up-regulation are not clearly understood. A potential physiological stimulus for MT1-MMP expression is fibrillar collagen, and it has been shown that it up-regulates both MT1-MMP gene and functions in various cell types. However, the mechanisms of collagen-mediated MT1-MMP activation and its physiological relevance are not known. In this study, we identified discoidin domain receptor 2 (DDR2) as a crucial receptor that mediates this process in human fibroblasts. Knocking down DDR2, but not the β1 integrin subunit, a common subunit for all collagen-binding integrins, inhibited the collagen-induced MT1-MMP-dependent activation of pro-MMP-2 and up-regulation of MT1-MMP at the gene and protein levels. Interestingly, DDR2 knockdown or pharmacological inhibition of DDR2 also inhibited the MT1-MMP-dependent cellular degradation of collagen film, suggesting that cell-surface collagen degradation by MT1-MMP involves DDR2-mediated collagen signaling. This DDR2-mediated mechanism is only present in non-transformed mesenchymal cells as collagen-induced MT1-MMP activation in HT1080 fibrosarcoma cells and MT1-MMP function in MDA-MB231 breast cancer cells were not affected by DDR kinase inhibition. DDR2 activation was found to be noticeably more effective when cells were stimulated by collagen without the non-helical telopeptide region compared with intact collagen fibrils. Furthermore, DDR2-dependent MT1-MMP activation by cartilage was found to be more efficient when the tissue was partially damaged. These data suggest that DDR2 is a microenvironment sensor that regulates fibroblast migration in a collagen-rich environment.
authors.affiliation: From the Kennedy Institute of Rheumatology, Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, United Kingdom and.
authors.forename: Iwona
authors.initials: I
authors.lastname: Majkowska
authors.affiliation: From the Kennedy Institute of Rheumatology, Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, United Kingdom and.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shitomi
authors.affiliation: From the Kennedy Institute of Rheumatology, Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, United Kingdom and.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ito
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Nathanael S
authors.identifier: 0000-0001-5354-7403
authors.initials: NS
authors.lastname: Gray
authors.affiliation: From the Kennedy Institute of Rheumatology, Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, United Kingdom and yoshi.itoh@kennedy.ox.ac.uk.
authors.forename: Yoshifumi
authors.identifier: 0000-0002-2128-2823
authors.initials: Y
authors.lastname: Itoh
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002356:Cartilage / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D024043:Collagen Type II / Q000378:metabolism*; D000070820:Discoidin Domain Receptor 2 / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005780:Gelatin / Q000737:chemistry; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D024043:Collagen Type II; D019012:Integrin beta1; D016023:Integrins; D034741:RNA, Small Interfering; D005780:Gelatin; C000603239:DDR2 protein, human; D000070820:Discoidin Domain Receptor 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: DDR2; MMP-2; MT1-MMP; arthritis; cancer; collagen; fibroblast; matrix metalloproteinase (MMP)