title: Shedding of discoidin domain receptor 1 by membrane-type matrix metalloproteinases.
abstract: The discoidin domain receptors (DDRs) are receptor tyrosine kinases that upon binding to collagens undergo receptor phosphorylation, which in turn activates signal transduction pathways that regulate cell-collagen interactions. We report here that collagen-dependent DDR1 activation is partly regulated by the proteolytic activity of the membrane-anchored collagenases, MT1-, MT2-, and MT3-matrix metalloproteinase (MMP). These collagenases cleave DDR1 and attenuate collagen I- and IV-induced receptor phosphorylation. This effect is not due to ligand degradation, as it proceeds even when the receptor is stimulated with collagenase-resistant collagen I (r/r) or with a triple-helical peptide harboring the DDR recognition motif in collagens. Moreover, the secreted collagenases MMP-1 and MMP-13 and the glycosylphosphatidylinositol-anchored membrane-type MMPs (MT4- and MT6-MMP) have no effect on DDR1 cleavage or activation. N-terminal sequencing of the MT1-MMP-mediated cleaved products and mutational analyses show that cleavage of DDR1 takes place within the extracellular juxtamembrane region, generating a membrane-anchored C-terminal fragment. Metalloproteinase inhibitor studies show that constitutive shedding of endogenous DDR1 in breast cancer HCC1806 cells is partly mediated by MT1-MMP, which also regulates collagen-induced receptor activation. Taken together, these data suggest a role for the collagenase of membrane-type MMPs in regulation of DDR1 cleavage and activation at the cell-matrix interface.
authors.affiliation: Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Hsueh-Liang
authors.initials: HL
authors.lastname: Fu
authors.forename: Anjum
authors.initials: A
authors.lastname: Sohail
authors.forename: Rajeshwari R
authors.initials: RR
authors.lastname: Valiathan
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Wasinski
authors.forename: Malika
authors.initials: M
authors.lastname: Kumarasiri
authors.forename: Kiran V
authors.initials: KV
authors.lastname: Mahasenan
authors.forename: M Margarida
authors.initials: MM
authors.lastname: Bernardo
authors.forename: Dorota
authors.initials: D
authors.lastname: Tokmina-Roszyk
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Fields
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.forename: Rafael
authors.initials: R
authors.lastname: Fridman
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D000070819:Discoidin Domain Receptor 1; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D017364:Collagenases