Cell surface collagenolysis requires homodimerization of the membrane-bound collagenase MT1-MMP.
Pericellular degradation of interstitial collagens is a crucial event for cells to migrate through the dense connective tissue matrices, where collagens exist as insoluble fibers. A key proteinase that participates in this process is considered to be membrane-type 1 matrix metalloproteinase (MT1-MMP or MMP-14), but little is known about the mechanism by which it cleaves the insoluble collagen. Here we report that homodimerization of MT1-MMP through its hemopexin (Hpx) domain is essential for cleaving type I collagen fibers at the cell surface. When dimerization was blocked by coexpressing either a membrane-bound or a soluble form of the Hpx domain, cell surface collagenolytic activity was inhibited in a dose-dependent manner. When MMP-13, a soluble collagenase active as a monomer in solution, was expressed as a membrane-anchored form on the cell surface, homodimerization was also required to cleave collagen. Our results introduce a new concept in that pericellular collagenolysis is regulated by correct molecular assembly of the membrane-anchored collagenase, thereby governing the directionality of the cell to migrate in tissue.
Itoh
Yoshifumi
Y
Department of Matrix Biology, Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London W6 8LH, United Kingdom. y.itoh@imperial.ac.uk
Ito
Noriko
N
Nagase
Hideaki
H
Evans
Richard D
RD
Bird
Sarah A
SA
Seiki
Motoharu
M
D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D024042:Collagen Type I / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism*; D019281:Dimerization; D004285:Dogs; D005782:Gels; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism
D024042:Collagen Type I; D005782:Gels; D008565:Membrane Proteins; D050505:Mutant Proteins; D011994:Recombinant Proteins; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14