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

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.

2003 ◽  
Vol 70 ◽  
pp. 253-262 ◽  
Author(s):  
Motoharu Seiki ◽  
Hidetoshi Mori ◽  
Masahiro Kajita ◽  
Takamasa Uekita ◽  
Yoshifumi Itoh

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.


2001 ◽  
Vol 153 (5) ◽  
pp. 893-904 ◽  
Author(s):  
Masahiro Kajita ◽  
Yoshifumi Itoh ◽  
Tadashige Chiba ◽  
Hidetoshi Mori ◽  
Akiko Okada ◽  
...  

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.


2004 ◽  
Vol 279 (14) ◽  
pp. 14129-14139 ◽  
Author(s):  
Jian Cao ◽  
Pallavi Kozarekar ◽  
Maria Pavlaki ◽  
Christian Chiarelli ◽  
Wadie F. Bahou ◽  
...  

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