Journal
GENE
Volume 788, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.gene.2021.145673
Keywords
DDR2; MT1-MMP; Collagen; DDR2-containing remnants; Metastasis
Categories
Funding
- National Program on Key Basic Research Project of China [2012CB518200]
- National Natural Science Foundation of China [31571231]
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The study found that collagen-activated DDR2 enhances the proteolytic activity of MT1-MMP, ensuring the continuous degradation of ECM in the remnants. This reveals a new alternative ECM degradation mechanism mediated by MT1-MMP.
Type I collagen is a major extracellular matrix (ECM) component in the interstitial stroma of solid tumors, and it represents the first barrier against tumor cell invasion after basement-membrane degradation. The collagen receptors that convey molecular signals into the cells are collagen-binding discoidin domain receptors (DDRs) and integrins. Collagen-activated DDR2 clusters form DDR2-containing remnants in an integrin-dependent manner in three-dimensional (3D) collagen matrix. Although DDR2-containing remnants in the collagen matrix may generate sustained perturbation to ECM remodeling, the molecular components and function of the remnants are largely unknown. Here we determined the interaction and co-localization between DDR2 and membrane type Imatrix metalloproteinase (MT1-MMP) in the cells and the DDR2-containing remnants on collagen fibers, and we found that MT1-MMP was co-tethered to collagen fibers in the remnants. These collagen fiber-associated MT1MMP remained active. Furthermore, DDR2 enhanced MT1-MMP proteolytic activity. These results demonstrate that DDR2 ensures the remnant-associated MT1-MMP to continue the degradation of ECM in addition to pericellular ECM degradation mediated by cell surface tethered MT1-MMP. Thus, our findings reveal a new alternative ECM degradation mechanism mediated by MT1-MMP in the DDR2-containing remnants.
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