Regulation of Discoidin Domain Receptor‐1 by Membrane‐type 1 Matrix Metalloproteinase (MT1‐MMP)

Abstract

Objective We investigated the effects of membrane type-matrix metalloproteinases (MT-MMPs) on the activation of discoidin domain receptors (DDRs), which are receptor tyrosine kinases (RTKs) that undergo receptor autophosphorylation in response to collagen. Methods Proteases were co-expressed with DDR1a or DDR1b and receptor phosphorylation in response to collagen was examined. Results we found that the transmembrane MT-MMPs, MT1-(MMP14), MT2- (MMP15), and MT3- (MMP16) MMP but not other members of the MT-MMP subfamily hinder collagen-dependent DDR1a/b activation and promote cleavage of the receptor ectodomain. Two soluble collagenases, MMP1 and MMP13, and a chimeric MT1-MMP containing the catalytic domain of MMP1 had no effect on DDR1 activation or cleavage, suggesting a specific effect of MT-MMPs on DDR1 regulation. T47D breast cancer cells expressing recombinant MT1-MMP exhibit reduced collagen-dependent phosphorylation and increased cleavage of endogenous DDR1. Conclusion These results show that DDR1a/b activation is specifically regulated by MT-MMPs and suggests that MT-MMP/DDR interactions may play a role in regulation of cell-collagen interactions during cell migration and invasion.