scholarly journals Membrane-type 1 matrix metalloproteinase (MMP-14) modulates tissue homeostasis by a non-proteolytic mechanism

2019 ◽  
Author(s):  
Mukundan Attur ◽  
Cuijie Lu ◽  
Xiaodong Zhang ◽  
Tianzhen Han ◽  
Cassidy Alexandre ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Intracellular Signaling ◽  
Cytoplasmic Tail ◽  
Tissue Homeostasis ◽  
Collagen Turnover ◽  
Wild Type ◽  
Ecm Remodeling ◽  
Membrane Type

SUMMARYMembrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane proteinase with a short cytoplasmic tail, is a major effector of extracellular matrix (ECM) remodeling. Genetic silencing of MT1-MMP in mouse (Mmp14−/−) and man causes dwarfism, osteopenia, arthritis and lipodystrophy, abnormalities ascribed to defective collagen turnover. We have previously shown non-proteolytic functions of MT1-MMP mediated by its cytoplasmic tail, where the unique tyrosine (Y573) controls intracellular signaling. The Y573D mutation blocks TIMP2/MT1-MMP-induced Erk1/2 and Akt signaling without affecting proteolytic activity. Here we report that a mouse with the MT1-MMP Y573D mutation (Mmp14Y573D/Y573D) shows abnormalities similar to, but also different from those of Mmp14−/− mice. Skeletal stem cells (SSC) of Mmp14Y573D/Y573D mice show defective differentiation consistent with the mouse phenotype, which is rescued by wild-type SSC transplant. These results provide the first in vivo demonstration that MT1-MMP modulates bone, cartilage and fat homeostasis by controlling SSC differentiation through a mechanism independent of proteolysis.

Immunohistochemical localization of membrane type 1-matrix metalloproteinase (MT1-MMP) in osteoclasts in vivo

2001 ◽  
Vol 33 (5) ◽  
pp. 478-482 ◽  
Author(s):  
K. Irie, ◽  
E. Tsuruga, ◽  
Y. Sakakura, ◽  
T. Muto, ◽  
T. Yajima
Keyword(s):  
Matrix Metalloproteinase ◽  
Immunohistochemical Localization ◽  
Membrane Type

Competitive disruption of the tumor-promoting function of membrane type 1 matrix metalloproteinase/matrix metalloproteinase-14 in vivo

2005 ◽  
Vol 4 (8) ◽  
pp. 1157-1166 ◽  
Author(s):  
Takahiro Nonaka ◽  
Kunika Nishibashi ◽  
Yoshifumi Itoh ◽  
Ikuo Yana ◽  
Motoharu Seiki
Keyword(s):  
Matrix Metalloproteinase ◽  
Membrane Type

scholarly journals Membrane type 1 matrix metalloproteinase (MT1-MMP) cleaves the recombinant aggrecan substrate rAgg1mut at the ‘aggrecanase’ and the MMP sites

1998 ◽  
Vol 333 (1) ◽  
pp. 159-165 ◽  
Author(s):  
Frank H. BÜTTNER ◽  
Clare E. HUGHES ◽  
Daniel MARGERIE ◽  
Andrea LICHTE ◽  
Harald TSCHESCHE ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Catalytic Domain ◽  
Human Articular Cartilage ◽  
Recombinant Enzymes ◽  
Recombinant Product ◽  
Weak Activity ◽  
Membrane Type

The recent detection of membrane type 1 matrix metalloproteinase (MT1-MMP) expression in human articular cartilage [Büttner, Chubinskaya, Margerie, Huch, Flechtenmacher, Cole, Kuettner, and Bartnik (1997) Arthritis Rheum. 40, 704–709] prompted our investigation of MT1-MMP's catabolic activity within the interglobular domain of aggrecan. For these studies we used rAgg1mut, a mutated form of the recombinant fusion protein (rAgg1) that has been used as a substrate to monitor ‘aggrecanase ’ catabolism in vitro [Hughes, Büttner, Eidenmüller, Caterson and Bartnik (1997) J. Biol. Chem. 272, 20269–20274]. The rAgg1 was mutated (G332 to A) to avoid the generation of a splice variant seen with the original genetic construct, which gave rise to heterogeneous glycoprotein products. This mutation yielded a homogeneous recombinant product. Studies in vitro with retinoic acid-stimulated rat chondrosarcoma cells indicated that the rAgg1mut substrate was cleaved at the ‘aggrecanase ’ site equivalent to Glu373-Ala374 (human aggrecan sequence enumeration) in its interglobular domain sequence segment. The differential catabolic activities of the recombinant catalytic domain (cd) of MT1-MMP and matrix metalloproteinases (MMPs) 3 and 8 were then compared by using this rAgg1mut as a substrate. Coomassie staining of rAgg1mut catabolites separated by SDS/PAGE showed similar patterns of degradation with all three recombinant enzymes. However, comparative immunodetection analysis, with neoepitope antibodies BC-3 (anti-ARGS …) and BC-14 (anti-FFGV …) to distinguish between ‘aggrecanase ’ and MMP-generated catabolites, indicated that the catalytic domain of MT1-MMP exhibited strong ‘aggrecanase ’ activity, cdMMP-8 weak activity and cdMMP-3 no activity. In contrast, cdMMP-3 and cdMMP-8 led to strongly BC-14-reactive catabolic fragments, whereas cdMT1-MMP resulted in weak BC-14 reactivity. N-terminal sequence analyses of the catabolites confirmed these results and also identified other potential minor cleavage sites within the interglobular domain of aggrecan. These results indicate that MT1-MMP is yet another candidate for ‘aggrecanase ’ activity in vivo.

scholarly journals Activation of Matrix-Metalloproteinase-2 and Membrane-Type-1-Matrix-Metalloproteinase in Endothelial Cells and Induction of Vascular Permeability In Vivo by Human Immunodeficiency Virus-1 Tat Protein and Basic Fibroblast Growth Factor

2001 ◽  
Vol 12 (10) ◽  
pp. 2934-2946 ◽  
Author(s):  
Elena Toschi ◽  
Giovanni Barillari ◽  
Cecilia Sgadari ◽  
Ilaria Bacigalupo ◽  
Anna Cereseto ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Fibroblast Growth ◽  
Tat Protein ◽  
Immunodeficiency Virus ◽  
Membrane Type ◽  
Hiv 1

Previous studies indicated that the Tat protein of human immunodeficiency virus type-1 (HIV-1) is a progression factor for Kaposi's sarcoma (KS). Specifically, extracellular Tat cooperates with basic fibroblast growth factor (bFGF) in promoting KS and endothelial cell growth and locomotion and in inducing KS-like lesions in vivo. Here we show that Tat and bFGF combined increase matrix-metalloproteinase-2 (MMP-2) secretion and activation in endothelial cells in an additive/synergistic manner. These effects are due to the activation of the membrane-type-1-matrix-metalloproteinase and to the induction of the membrane-bound tissue inhibitor of metalloproteinase-2 (TIMP-2) by Tat and bFGF combined, but also to Tat-mediated inhibition of both basal or bFGF-induced TIMP-1 and -2 secretion. Consistent with this, Tat and bFGF promote vascular permeability and edema in vivo that are blocked by a synthetic MMP inhibitor. Finally, high MMP-2 expression is detected in acquired immunodeficiency virus syndrome (AIDS)-KS lesions, and increased levels of MMP-2 are found in plasma from patients with AIDS-KS compared with HIV-uninfected individuals with classic KS, indicating that these mechanisms are operative in AIDS-KS. This suggests a novel pathway by which Tat can increase KS aggressiveness or induce vasculopathy in the setting of HIV-1 infection.

scholarly journals Membrane-type 1 Matrix Metalloproteinase Modulates Tissue Homeostasis by a Non-proteolytic Mechanism

iScience ◽  
2020 ◽  
Vol 23 (12) ◽  
pp. 101789
Author(s):  
Mukundan Attur ◽  
Cuijie Lu ◽  
Xiaodong Zhang ◽  
Tianzhen Han ◽  
Cassidy Alexandre ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Tissue Homeostasis ◽  
Membrane Type

scholarly journals Direct regulation of membrane type 1 matrix metalloproteinase following myocardial infarction causes changes in survival, cardiac function, and remodeling

2011 ◽  
Vol 301 (4) ◽  
pp. H1656-H1666 ◽  
Author(s):  
Juozas A. Zavadzkas ◽  
Rupak Mukherjee ◽  
William T. Rivers ◽  
Risha K. Patel ◽  
Evan C. Meyer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Transforming Growth Factor ◽  
Biological Effects ◽  
Left Ventricular ◽  
Lv Function ◽  
Membrane Type

The membrane type 1 matrix metalloproteinase (MT1-MMP) is increased in left ventricular (LV) failure. However, the direct effects of altered MT1-MMP levels on survival, LV function, and geometry following myocardial infarction (MI) and the proteolytic substrates involved in this process remain unclear. MI was induced in mice with cardiac-restricted overexpression of MT1-MMP (MT1-MMPexp; full length human), reduced MT1-MMP expression (heterozygous; MT1-MMP+/−), and wild type. Post-MI survival was reduced with MT1-MMPexp and increased with MT1-MMP+/− compared with WT. LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT post-MI and was higher in the MT1-MMP+/− mice. In vivo localization of MT1-MMP using antibody-conjugated microbubbles revealed higher MT1-MMP levels post-MI, which were the highest in the MT1-MMPexp group and the lowest in the MT1-MMP+/− group. LV collagen content within the MI region was higher in the MT1-MMPexp vs. WT post-MI and reduced in the MT1-MMP+/− group. Furthermore, it was demonstrated that MT1-MMP proteolytically processed the profibrotic molecule, latency-associated transforming growth factor-1-binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by over fourfold in the post-MI MT1-MMPexp group and reduced in the MT1-MMP+/− group, which was directionally paralleled by phospho-Smad-3 levels, a critical signaling component of the profibrotic transforming growth factor pathway. We conclude that modulating myocardial MT1-MMP levels affected LV function and matrix structure, and a contributory mechanism for these effects is through processing of profibrotic signaling molecules. These findings underscore the diversity of biological effects of certain MMP types on the LV remodeling process.

Sign in / Sign up

Export Citation Format

Share Document