DOI: 10.1073/pnas.94.15.7959. Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion

Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion

10.1073/pnas.94.15.7959

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The invasion of human malignant melanoma cells into the extracellular matrix (ECM) involves the accumulation of proteases at sites of ECM degradation where activation of matrix metalloproteases (MMP) occurs. Here, we show that when membrane type 1 MMP (MT-MMP) was overexpressed in RPMI7951 human melanoma cells, the cells made contact with the ECM, activated soluble and ECM-bound MMP-2, and degraded and invaded the ECM. Further experiments demonstrated the importance of localization of the MT-MMP to invadopodia. Overexpression of MT-MMP without invadopodial localization caused activation of soluble MMP-2, but did not facilitate ECM degradation or cell invasiveness. Up-regulation of endogenous MT-MMP with concanavalin A caused activation of MMP-2. However, concanavalin A treatment prevented invadopodial localization of MT-MMP and ECM degradation. Neither a truncated MT-MMP mutant lacking transmembrane (TM) and cytoplasmic domains (ΔTM MT-MMP ), nor a chimeric MT-MMP containing the interleukin 2 receptor α chain (IL-2R) TM and cytoplasmic domains (ΔTM MT-MMP /TM IL-2R ) were localized to invadopodia or exhibited ECM degradation. Furthermore, a chimera of the TM/cytoplasmic domain of MT-MMP (TM MT-MMP ) with tissue inhibitor of MMP 1 (TIMP-1/TM MT-MMP ) directed the TIMP-1 molecule to invadopodia. Thus, the MT-MMP TM/cytoplasmic domain mediates the spatial organization of MT-MMP into invadopodia and subsequent degradation of the ECM.

Bibliography

Nakahara, H., Howard, L., Thompson, E. W., Sato, H., Seiki, M., Yeh, Y., & Chen, W.-T. (1997). Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cellâinvasion. Proceedings of the National Academy of Sciences, 94(15), 7959â7964.

Authors 7

Hirokazu Nakahara (first)
Linda Howard (additional)
Erik W. Thompson (additional)
Hiroshi Sato (additional)
Motoharu Seiki (additional)
Yunyun Yeh (additional)
Wen-Tien Chen (additional)

References 31 Referenced 329

10.1152/physrev.1993.73.1.161
10.1146/annurev.cb.09.110193.002545
10.1007/BF00666155
10.1042/bst0220055
10.1177/10454411930040020401
H S Azzam, E W Thompson Cancer Res 52, 4540–4544 (1992). / Cancer Res by Azzam H S (1992)
W L Monsky, T Kelly, C Y Lin, Y Yeh, W G Stetler-Stevenson, S C Mueller, W-T Chen Cancer Res 53, 3159–3164 (1993). / Cancer Res by Monsky W L (1993)
M Yu, H Sato, M Seiki, E W Thompson Cancer Res 55, 3272–3277 (1995). / Cancer Res by Yu M (1995)
10.1093/jnci/85.21.1758
X Wang, X Fu, P D Brown, M J Crimmin, R M Hoffman Cancer Res 54, 4726–4728 (1994). / Cancer Res by Wang X (1994)
10.1016/0378-1119(89)90359-4
10.1074/jbc.270.10.5331
10.1038/370061a0
10.1073/pnas.92.7.2730
10.1016/0014-5793(96)00389-4
10.1074/jbc.271.15.9135
K Imai, E Ohuchi, T Aoki, H Nomura, Y Fujii, H Sato, M Seiki, Y Okada Cancer Res 56, 2707–2710 (1996). / Cancer Res by Imai K (1996)
10.1074/jbc.272.4.2446
W L Monsky, C-Y Lin, A Aoyama, T Kelly, S C Mueller, S K Akiyama, W-T Chen Cancer Res 54, 5702–5710 (1994). / Cancer Res by Monsky W L (1994)
J R Morphy, T A Millican Curr Med Chem 2, 743–762 (1996). (10.2174/092986730203220224091658) / Curr Med Chem by Morphy J R (1996)
10.1073/pnas.87.21.8296
10.1007/BF01540646
10.1074/jbc.270.2.801
10.1083/jcb.119.5.1309
10.1002/jez.1402510206
10.1159/000468616
10.1074/jbc.271.44.27221
10.1074/jbc.272.12.7595
10.1007/BF01833261
10.1074/jbc.270.19.11555
A R Mackay, D E Gomez, D W Cottam, R C Rees, A M Nason, U P Thorgeirsson BioTechniques 15, 1048–1051 (1993). / BioTechniques by Mackay A R (1993)

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:42 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 3:18 p.m.)
Indexed	1 month, 3 weeks ago (July 12, 2025, 6:58 p.m.)
Issued	28 years, 1 month ago (July 22, 1997)
Published	28 years, 1 month ago (July 22, 1997)
Published Online	28 years, 1 month ago (July 22, 1997)
Published Print	28 years, 1 month ago (July 22, 1997)

Funders 0

None

BibTeX

@article{Nakahara_1997, title={Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion}, volume={94}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.94.15.7959}, DOI={10.1073/pnas.94.15.7959}, number={15}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Nakahara, Hirokazu and Howard, Linda and Thompson, Erik W. and Sato, Hiroshi and Seiki, Motoharu and Yeh, Yunyun and Chen, Wen-Tien}, year={1997}, month=jul, pages={7959–7964} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        12
      ]
    ],
    "date-time": "2025-07-12T22:58:26Z",
    "timestamp": 1752361106617
  },
  "reference-count": 31,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "15",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        1997,
        7,
        22
      ]
    ]
  },
  "abstract": "<jats:p>\n            The invasion of human malignant melanoma cells into the extracellular matrix (ECM) involves the accumulation of proteases at sites of ECM degradation where activation of matrix metalloproteases (MMP) occurs. Here, we show that when membrane type 1 MMP (MT-MMP) was overexpressed in RPMI7951 human melanoma cells, the cells made contact with the ECM, activated soluble and ECM-bound MMP-2, and degraded and invaded the ECM. Further experiments demonstrated the importance of localization of the MT-MMP to invadopodia. Overexpression of MT-MMP without invadopodial localization caused activation of soluble MMP-2, but did not facilitate ECM degradation or cell invasiveness. Up-regulation of endogenous MT-MMP with concanavalin A caused activation of MMP-2. However, concanavalin A treatment prevented invadopodial localization of MT-MMP and ECM degradation. Neither a truncated MT-MMP mutant lacking transmembrane (TM) and cytoplasmic domains (\u0394TM\n            <jats:sub>MT-MMP</jats:sub>\n            ), nor a chimeric MT-MMP containing the interleukin 2 receptor \u03b1 chain (IL-2R) TM and cytoplasmic domains (\u0394TM\n            <jats:sub>MT-MMP</jats:sub>\n            /TM\n            <jats:sub>IL-2R</jats:sub>\n            ) were localized to invadopodia or exhibited ECM degradation. Furthermore, a chimera of the TM/cytoplasmic domain of MT-MMP (TM\n            <jats:sub>MT-MMP</jats:sub>\n            ) with tissue inhibitor of MMP 1 (TIMP-1/TM\n            <jats:sub>MT-MMP</jats:sub>\n            ) directed the TIMP-1 molecule to invadopodia. Thus, the MT-MMP TM/cytoplasmic domain mediates the spatial organization of MT-MMP into invadopodia and subsequent degradation of the ECM.\n          </jats:p>",
  "DOI": "10.1073/pnas.94.15.7959",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2002,
        7,
        26
      ]
    ],
    "date-time": "2002-07-26T14:42:40Z",
    "timestamp": 1027694560000
  },
  "page": "7959-7964",
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 329,
  "title": "Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required  for cell\u2009invasion",
  "prefix": "10.1073",
  "volume": "94",
  "author": [
    {
      "given": "Hirokazu",
      "family": "Nakahara",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Lombardi Cancer Center and Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007; and Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, 920, Japan"
        }
      ]
    },
    {
      "given": "Linda",
      "family": "Howard",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Lombardi Cancer Center and Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007; and Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, 920, Japan"
        }
      ]
    },
    {
      "given": "Erik W.",
      "family": "Thompson",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Lombardi Cancer Center and Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007; and Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, 920, Japan"
        }
      ]
    },
    {
      "given": "Hiroshi",
      "family": "Sato",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Lombardi Cancer Center and Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007; and Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, 920, Japan"
        }
      ]
    },
    {
      "given": "Motoharu",
      "family": "Seiki",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Lombardi Cancer Center and Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007; and Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, 920, Japan"
        }
      ]
    },
    {
      "given": "Yunyun",
      "family": "Yeh",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Lombardi Cancer Center and Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007; and Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, 920, Japan"
        }
      ]
    },
    {
      "given": "Wen-Tien",
      "family": "Chen",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Lombardi Cancer Center and Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007; and Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, 920, Japan"
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        1997,
        7,
        22
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_3_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1152/physrev.1993.73.1.161"
    },
    {
      "key": "e_1_3_3_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1146/annurev.cb.09.110193.002545"
    },
    {
      "key": "e_1_3_3_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/BF00666155"
    },
    {
      "key": "e_1_3_3_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1042/bst0220055"
    },
    {
      "key": "e_1_3_3_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1177/10454411930040020401"
    },
    {
      "key": "e_1_3_3_6_2",
      "first-page": "4540",
      "volume": "52",
      "author": "Azzam H S",
      "year": "1992",
      "unstructured": "H S Azzam, E W Thompson Cancer Res 52, 4540\u20134544 (1992).",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_3_3_7_2",
      "first-page": "3159",
      "volume": "53",
      "author": "Monsky W L",
      "year": "1993",
      "unstructured": "W L Monsky, T Kelly, C Y Lin, Y Yeh, W G Stetler-Stevenson, S C Mueller, W-T Chen Cancer Res 53, 3159\u20133164 (1993).",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_3_3_8_2",
      "first-page": "3272",
      "volume": "55",
      "author": "Yu M",
      "year": "1995",
      "unstructured": "M Yu, H Sato, M Seiki, E W Thompson Cancer Res 55, 3272\u20133277 (1995).",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_3_3_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1093/jnci/85.21.1758"
    },
    {
      "key": "e_1_3_3_10_2",
      "first-page": "4726",
      "volume": "54",
      "author": "Wang X",
      "year": "1994",
      "unstructured": "X Wang, X Fu, P D Brown, M J Crimmin, R M Hoffman Cancer Res 54, 4726\u20134728 (1994).",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_3_3_11_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0378-1119(89)90359-4"
    },
    {
      "key": "e_1_3_3_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.270.10.5331"
    },
    {
      "key": "e_1_3_3_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/370061a0"
    },
    {
      "key": "e_1_3_3_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.92.7.2730"
    },
    {
      "key": "e_1_3_3_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0014-5793(96)00389-4"
    },
    {
      "key": "e_1_3_3_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.271.15.9135"
    },
    {
      "key": "e_1_3_3_17_2",
      "first-page": "2707",
      "volume": "56",
      "author": "Imai K",
      "year": "1996",
      "unstructured": "K Imai, E Ohuchi, T Aoki, H Nomura, Y Fujii, H Sato, M Seiki, Y Okada Cancer Res 56, 2707\u20132710 (1996).",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_3_3_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.272.4.2446"
    },
    {
      "key": "e_1_3_3_19_2",
      "first-page": "5702",
      "volume": "54",
      "author": "Monsky W L",
      "year": "1994",
      "unstructured": "W L Monsky, C-Y Lin, A Aoyama, T Kelly, S C Mueller, S K Akiyama, W-T Chen Cancer Res 54, 5702\u20135710 (1994).",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_3_3_20_2",
      "doi-asserted-by": "crossref",
      "first-page": "743",
      "DOI": "10.2174/092986730203220224091658",
      "volume": "2",
      "author": "Morphy J R",
      "year": "1996",
      "unstructured": "J R Morphy, T A Millican Curr Med Chem 2, 743\u2013762 (1996).",
      "journal-title": "Curr Med Chem"
    },
    {
      "key": "e_1_3_3_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.87.21.8296"
    },
    {
      "key": "e_1_3_3_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/BF01540646"
    },
    {
      "key": "e_1_3_3_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.270.2.801"
    },
    {
      "key": "e_1_3_3_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.119.5.1309"
    },
    {
      "key": "e_1_3_3_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/jez.1402510206"
    },
    {
      "key": "e_1_3_3_26_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1159/000468616"
    },
    {
      "key": "e_1_3_3_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.271.44.27221"
    },
    {
      "key": "e_1_3_3_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.272.12.7595"
    },
    {
      "key": "e_1_3_3_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1007/BF01833261"
    },
    {
      "key": "e_1_3_3_30_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.270.19.11555"
    },
    {
      "key": "e_1_3_3_31_2",
      "first-page": "1048",
      "volume": "15",
      "author": "Mackay A R",
      "year": "1993",
      "unstructured": "A R Mackay, D E Gomez, D W Cottam, R C Rees, A M Nason, U P Thorgeirsson BioTechniques 15, 1048\u20131051 (1993).",
      "journal-title": "BioTechniques"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.94.15.7959",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        4,
        13
      ]
    ],
    "date-time": "2022-04-13T19:18:50Z",
    "timestamp": 1649877530000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.94.15.7959"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        1997,
        7,
        22
      ]
    ]
  },
  "references-count": 31,
  "journal-issue": {
    "issue": "15",
    "published-print": {
      "date-parts": [
        [
          1997,
          7,
          22
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.94.15.7959"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.94.15.7959",
  "relation": {},
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        1997,
        7,
        22
      ]
    ]
  },
  "assertion": [
    {
      "value": "1996-08-26",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "1997-05-19",
      "order": 1,
      "name": "accepted",
      "label": "Accepted",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "1997-07-22",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}