Membrane-type 1 matrix metalloproteinase and cell migration

2003 ◽  
Vol 70 ◽  
pp. 253-262 ◽  
Author(s):  
Motoharu Seiki ◽  
Hidetoshi Mori ◽  
Masahiro Kajita ◽  
Takamasa Uekita ◽  
Yoshifumi Itoh
Keyword(s):  
Cell Migration ◽  
Matrix Metalloproteinase ◽  
Malignant Tumour ◽  
Surface Proteins ◽  
Migration And Invasion ◽  
Cellular Functions ◽  
Cell Surface Proteins ◽  
Extracellular Stimuli ◽  
Membrane Type

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is an integral membrane proteinase that performs processing of cell surface proteins and degradation of extracellular matrix (ECM) components. Through these proteolytic events, MT1-MMP regulates various cellular functions, including ECM turnover, promotion of cell migration and invasion, and morphogenic responses to extracellular stimuli. MT1-MMP has to be regulated strictly to accomplish its function appropriately at various steps, including at the transcriptional and post-translational levels. MT1-MMP was originally identified as an invasion-promoting enzyme expressed in malignant tumour cells, and also as a specific activator of proMMP-2, which is believed to play a role in invasion of the basement membrane. Since then, it has attracted attention as a membrane-associated MMP that promotes cancer cell invasion and angiogenesis by endothelial cells. Although MT1-MMP has now become one of the best characterized enzymes in the MMP family, there remain numerous unanswered questions. In this chapter, we summarize our recent findings on how MT1-MMP is regulated during cell migration, and how cell migration is regulated by MT1-MMP.

scholarly journals Cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity

2001 ◽  
Vol 155 (7) ◽  
pp. 1345-1356 ◽  
Author(s):  
Takamasa Uekita ◽  
Yoshifumi Itoh ◽  
Ikuo Yana ◽  
Hiroshi Ohno ◽  
Motoharu Seiki
Keyword(s):  
Cell Migration ◽  
Matrix Metalloproteinase ◽  
Adaptor Protein ◽  
Cytoplasmic Tail ◽  
Migration And Invasion ◽  
Coated Pits ◽  
Cell Migration And Invasion ◽  
Promote Cell Migration ◽  
Membrane Type

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is an integral membrane proteinase that degrades the pericellular extracellular matrix (ECM) and is expressed in many migratory cells, including invasive cancer cells. MT1-MMP has been shown to localize at the migration edge and to promote cell migration; however, it is not clear how the enzyme is regulated during the migration process. Here, we report that MT1-MMP is internalized from the surface and that this event depends on the sequence of its cytoplasmic tail. Di-leucine (Leu571–572 and Leu578–579) and tyrosine573 residues are important for the internalization, and the μ2 subunit of adaptor protein 2, a component of clathrin-coated pits for membrane protein internalization, was found to bind to the LLY573 sequence. MT1-MMP was internalized predominantly at the adherent edge and was found to colocalize with clathrin-coated vesicles. The mutations that disturb internalization caused accumulation of the enzyme at the adherent edge, though the net proteolytic activity was not affected much. Interestingly, whereas expression of MT1-MMP enhances cell migration and invasion, the internalization-defective mutants failed to promote either activity. These data indicate that dynamic turnover of MT1-MMP at the migration edge by internalization is important for proper enzyme function during cell migration and invasion.

scholarly journals Membrane-Type 1 Matrix Metalloproteinase Cleaves Cd44 and Promotes Cell Migration

2001 ◽  
Vol 153 (5) ◽  
pp. 893-904 ◽  
Author(s):  
Masahiro Kajita ◽  
Yoshifumi Itoh ◽  
Tadashige Chiba ◽  
Hidetoshi Mori ◽  
Akiko Okada ◽  
...  
Keyword(s):  
Cell Migration ◽  
Matrix Metalloproteinase ◽  
Tumor Cell ◽  
Cell Motility ◽  
Tumor Cell Line ◽  
Dominant Negative ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Membrane Type

Migratory cells including invasive tumor cells frequently express CD44, a major receptor for hyaluronan and membrane-type 1 matrix metalloproteinase (MT1-MMP) that degrades extracellular matrix at the pericellular region. In this study, we demonstrate that MT1-MMP acts as a processing enzyme for CD44H, releasing it into the medium as a soluble 70-kD fragment. Furthermore, this processing event stimulates cell motility; however, expression of either CD44H or MT1-MMP alone did not stimulate cell motility. Coexpression of MT1-MMP and mutant CD44H lacking the MT1-MMP–processing site did not result in shedding and did not promote cell migration, suggesting that the processing of CD44H by MT1-MMP is critical in the migratory stimulation. Moreover, expression of the mutant CD44H inhibited the cell migration promoted by CD44H and MT1-MMP in a dominant-negative manner. The pancreatic tumor cell line, MIA PaCa-2, was found to shed the 70-kD CD44H fragment in a MT1-MMP–dependent manner. Expression of the mutant CD44H in the cells as well as MMP inhibitor treatment effectively inhibited the migration, suggesting that MIA PaCa-2 cells indeed use the CD44H and MT1-MMP as migratory devices. These findings revealed a novel interaction of the two molecules that have each been implicated in tumor cell migration and invasion.

scholarly journals Distinct Roles for the Catalytic and Hemopexin Domains of Membrane Type 1-Matrix Metalloproteinase in Substrate Degradation and Cell Migration

2004 ◽  
Vol 279 (14) ◽  
pp. 14129-14139 ◽  
Author(s):  
Jian Cao ◽  
Pallavi Kozarekar ◽  
Maria Pavlaki ◽  
Christian Chiarelli ◽  
Wadie F. Bahou ◽  
...  
Keyword(s):  
Cell Migration ◽  
Matrix Metalloproteinase ◽  
Substrate Degradation ◽  
Membrane Type

scholarly journals Notch1 Autoactivation via Transcriptional Regulation of Furin, Which Sustains Notch1 Signaling by Processing Notch1-Activating Proteases ADAM10 and Membrane Type 1 Matrix Metalloproteinase

2015 ◽  
Vol 35 (21) ◽  
pp. 3622-3632 ◽  
Author(s):  
Hong Qiu ◽  
Xiaoying Tang ◽  
Jun Ma ◽  
Khvaramze Shaverdashvili ◽  
Keman Zhang ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Chromatin Immunoprecipitation ◽  
Biologically Active ◽  
Migration And Invasion ◽  
Melanoma Tumor ◽  
Notch1 Signaling ◽  
Notch Intracellular Domain ◽  
Evolutionarily Conserved ◽  
Membrane Type

Notch1 is an evolutionarily conserved transmembrane receptor involved in melanoma growth. Notch1 is first cleaved by furin in the Golgi apparatus to produce the biologically active heterodimer. Following ligand binding, Notch1 is cleaved at the cell membrane by proteases such as ADAM10 and -17 and membrane type 1 matrix metalloproteinase (MT1-MMP), the latter of which we recently identified as a novel protease involved in Notch1 processing. The final cleavage is γ-secretase dependent and releases the active Notch intracellular domain (NIC). We now demonstrate that Notch1 directly regulates furin expression. Aside from activating Notch1, furin cleaves and activates several proteases, including MT1-MMP, ADAM10, and ADAM17. By chromatin immunoprecipitation and a reporter assay, we demonstrate that Notch1 binds at position −1236 of the furin promoter and drives furin expression. The Notch1-dependent enhancement of furin expression increases the activities of MT1-MMP and ADAM10 but not that of ADAM17, as demonstrated by short hairpin RNA (shRNA) knockdown of furin, and promotes the cleavage of Notch1 itself. These data highlight a novel positive-feedback loop whereby Notch1-dependent furin expression can induce Notch1 signaling by increasing Notch1 processing and by potentiating the activity of the proteases responsible for Notch1 activation. This leads to Notch1 signal amplification, which can promote melanoma tumor growth and progression, as demonstrated by the inhibition of cell migration and invasion upon furin inhibition downstream of Notch1. Disruption of such feedback signaling might represent an avenue for the treatment of melanoma.

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