Unknown

Dataset Information

0

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.

SUBMITTER: Fu HL 

PROVIDER: S-EPMC3636896 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 recept  ...[more]

Similar Datasets

| S-EPMC4638154 | biostudies-literature
| S-EPMC2593136 | biostudies-literature
| S-EPMC7994674 | biostudies-literature
| S-EPMC3191873 | biostudies-literature
| S-EPMC5605405 | biostudies-literature
| S-EPMC6727269 | biostudies-literature
| S-EPMC6965760 | biostudies-literature
| S-EPMC6320373 | biostudies-literature
| S-EPMC7750578 | biostudies-literature
| S-EPMC4325837 | biostudies-literature