Molecular Dissection of the Structural Machinery Underlying the Tissue-invasive Activity of Membrane Type-1 Matrix Metalloproteinase

Authors:
Li XY, Ota I, Yana I, Sabeh F, Weiss SJ
In:
Source: Mol Biol Cell
Publication Date: (2008)
Issue: 19(8): 3221-33
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
HT-1080
Species: human
Tissue Origin: bone
Platform:
Nucleofector® I/II/2b
Abstract
Membrane type-I 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 2-D culture conditions, MT1-MMP is categorized as a multifunctional molecule with i) a structurally distinct, N-terminal catalytic domain ii) a C-terminal hemopexin domain that regulates substrate recognition as well as conformation and iii) 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 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.