Molecular dissection of the structural machinery underlying the tissue-invasive activity of membrane type-1 matrix metalloproteinase.
Membrane type-1 matrix metalloproteinase (MT1-MMP) drives cell invasion through three-dimensional (3-D) extracellular matrix (ECM) barriers dominated by type I collagen or fibrin. Based largely on analyses of its impact on cell function under two-dimensional culture conditions, MT1-MMP is categorized as a multifunctional molecule with 1) a structurally distinct, N-terminal catalytic domain; 2) a C-terminal hemopexin domain that regulates substrate recognition as well as conformation; and 3) a type I transmembrane domain whose cytosolic tail controls protease trafficking and signaling cascades. The MT1-MMP domains that subserve cell trafficking through 3-D ECM barriers in vitro or in vivo, however, remain largely undefined. Herein, we demonstrate that collagen-invasive activity is not confined strictly to the catalytic, hemopexin, transmembrane, or cytosolic domain sequences of MT1-MMP. Indeed, even a secreted collagenase supports invasion when tethered to the cell surface in the absence of the MT1-MMP hemopexin, transmembrane, and cytosolic tail domains. By contrast, the ability of MT1-MMP to support fibrin-invasive activity diverges from collagenolytic potential, and alternatively, it requires the specific participation of MT-MMP catalytic and hemopexin domains. Hence, the tissue-invasive properties of MT1-MMP are unexpectedly embedded within distinct, but parsimonious, sequences that serve to tether the requisite matrix-degradative activity to the surface of migrating cells.
Li
Xiao-Yan
XY
Division of Molecular Medicine and Genetics, Department of Internal Medicine, The Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Ota
Ichiro
I
Yana
Ikuo
I
Sabeh
Farideh
F
Weiss
Stephen J
SJ
D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D003094:Collagen / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006466:Hemopexin / Q000378:metabolism; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
D003094:Collagen; D006466:Hemopexin; D053511:Matrix Metalloproteinase 14