Shedding of discoidin domain receptor 1 by membrane-type matrix metalloproteinases.

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.

Angiotensin-converting enzyme inhibitors increase anti-fibrotic biomarkers in African Americans with left ventricular hypertrophy.

Angiotensin-converting enzyme inhibitors (ACEi) are part of the indicated treatment in hypertensive African Americans. ACEi have blood pressure-independent effects that may make them preferred for certain patients. We aimed to evaluate the impact of ACEi on anti-fibrotic biomarkers in African American hypertensive patients with left ventricular hypertrophy (LVH). We conducted a post hoc analysis of a randomized controlled trial in which hypertensive African American patients with LVH and vitamin D deficiency were randomized to receive intensive antihypertensive therapy plus vitamin D supplementation or placebo. We selected patients who had detectable lisinopril (lisinopril group) in plasma using liquid-chromatography/mass spectrometry analysis and compared them to subjects who did not (comparison group) at the one-year follow-up. The pro-fibrotic marker type 1 procollagen C-terminal propeptide (PICP) and the anti-fibrotic markers matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinases 1 (TIMP-1), telopeptide of collagen type I (CITP), and N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) peptide were measured. Sixty-six patients were included, and the mean age was 46.2 ± 8 years. No difference was observed in the number and intensity of antihypertensive medications prescribed in each group. Patients with detectable lisinopril had lower blood pressure than those in the comparison group. The anti-fibrotic markers Ac-SDKP, MMP-1, and MMP-1/TIMP-1 ratio were higher in patients with detectable ACEi (all p < .05). In a model adjusted for systolic blood pressure, MMP-1/TIMP-1 (p = .02) and Ac-SDKP (p < .001) levels were associated with lisinopril. We conclude that ACEi increase anti-fibrotic biomarkers in hypertensive African Americans with LVH, suggesting that they may offer added benefit over other agents in such patients.

Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts.

The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen. Using an inducible expression system in human HT1080 fibrosarcoma cells, we investigated the role of DDR1b and DDR2 on primary tumour growth and experimental lung metastases. Neither DDR1b nor DDR2 expression altered tumour growth at the primary site. However, implantation of DDR1b- or DDR2-expressing HT1080 cells with collagen I significantly accelerated tumour growth rate, an effect that could not be observed with collagen I in the absence of DDR induction. Interestingly, DDR1b, but not DDR2, completely hindered the ability of HT1080 cells to form lung colonies after intravenous inoculation, suggesting a differential role for DDR1b in primary tumour growth and lung colonization. Analyses of tumour extracts revealed specific alterations in Hippo pathway core components, as a function of DDR and collagen expression, that were associated with stimulation of tumour growth by DDRs and collagen I. Collectively, these findings identified divergent effects of DDRs on primary tumour growth and experimental lung metastasis in the HT1080 xenograft model and highlight the critical role of fibrillar collagen and DDRs in supporting the growth of tumours thriving within a collagen-rich stroma.