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

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 migr...

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Autores principales: Uekita, Takamasa, Itoh, Yoshifumi, Yana, Ikuo, Ohno, Hiroshi, Seiki, Motoharu
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2001
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199326/
https://www.ncbi.nlm.nih.gov/pubmed/11756481
http://dx.doi.org/10.1083/jcb.200108112
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author Uekita, Takamasa
Itoh, Yoshifumi
Yana, Ikuo
Ohno, Hiroshi
Seiki, Motoharu
author_facet Uekita, Takamasa
Itoh, Yoshifumi
Yana, Ikuo
Ohno, Hiroshi
Seiki, Motoharu
author_sort Uekita, Takamasa
collection PubMed
description 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 (Leu(571–572) and Leu(578–579)) and tyrosine(573) 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 LLY(573) 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.
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spelling pubmed-21993262008-05-01 Cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity Uekita, Takamasa Itoh, Yoshifumi Yana, Ikuo Ohno, Hiroshi Seiki, Motoharu J Cell Biol Article 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 (Leu(571–572) and Leu(578–579)) and tyrosine(573) 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 LLY(573) 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. The Rockefeller University Press 2001-12-24 /pmc/articles/PMC2199326/ /pubmed/11756481 http://dx.doi.org/10.1083/jcb.200108112 Text en Copyright © 2001, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Uekita, Takamasa
Itoh, Yoshifumi
Yana, Ikuo
Ohno, Hiroshi
Seiki, Motoharu
Cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity
title Cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity
title_full Cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity
title_fullStr Cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity
title_full_unstemmed Cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity
title_short Cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity
title_sort cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199326/
https://www.ncbi.nlm.nih.gov/pubmed/11756481
http://dx.doi.org/10.1083/jcb.200108112
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