Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration

Oncogene volume 18, pages 1435–1446 (1999)Cite this article

Abstract

CD44 is a cell surface receptor for hyaluronate, a component of the extracellular matrix (ECM). Although CD44 has been implicated in tumor invasion and metastasis, the molecular mechanisms remain to be elucidated. Here we find that CD44 expressed in cancer cells is cleaved at the membrane-proximal region of the ectodomain and the membrane-bound cleavage product can be detected using an antibody against the cytoplasmic domain of CD44. Furthermore, we report that CD44 cleavage is mediated by a membrane-associated metalloprotease expressed in cancer cells. A tissue inhibitor of metalloproteases-1 (TIMP-1), as well as metalloprotease inhibitors, inhibit CD44 cleavage in the cell-free assay. Contrary, serine protease inhibitors enhance CD44 cleavage, and the enhancement can be prevented by pretreatment with a metalloprotease inhibitor. Thus, CD44 cleavage is regulated by an intricate balance between some proteases and their inhibitors. Interestingly, treatment with the metalloprotease blocker 1,10-phenanthroline, which strongly prevent the CD44 cleavage, suppressed RERF-LC-OK lung cancer cell migration on a hyaluronate substrate, but not on several other substrates. These results suggest that CD44 cleavage plays a critical role in an efficient cell-detachment from a hyaluronate substrate during the cell migration and consequently promotes CD44-mediated cancer cell migration. Our present data indicate that CD44, not only ECM per se, is one of the targets of pericellular proteolysis involved in tumor invasion and metastasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

References

  • Albelda SM. . 1993 Lab. Invest. 68: 4–17.

  • Amano M, Chihara K, Kimura K, Fukata Y, Nakamura N, Matsuura Y and Kaibuchi K. . 1997 Science 275: 1308–1311.

    Article  CAS  Google Scholar 

  • Arch R, Wirth K, Hofmann M, Ponta H, Matzku S, Herrlich P and Zöller M. . 1992 Science 257: 682–685.

    Article  CAS  Google Scholar 

  • Aruffo A, Stamenkovic I, Melnick M, Underhill CB and Seed B. . 1990 Cell 61: 1303–1313.

    Article  CAS  Google Scholar 

  • Bartolazzi A, Jackson D, Bennett K, Aruffo A, Dickinson R, Shields J, Whittle N and Stamenkovic I. . 1995 J. Cell Sci. 108: 1723–1733.

  • Bartolazzi A, Nocks A, Aruffo A, Spring F and Stamenkovic I. . 1996 J. Cell Biol. 132: 1199–1208.

  • Bartolazzi A, Peach R, Aruffo A and Stamenkovic I. . 1994 J. Exp. Med. 180: 53–66.

  • Bazil V and Strominger JL. . 1994 J. Immunol. 152: 1314–1322.

  • Bennett KL, Modrell B, Greenfield B, Bartolazzi A, Stamenkovic I, Peach R, Jackson DG, Spring F and Aruffo A. . 1995 J. Cell Biol. 131: 1623–1633.

  • Chambers AF and Matrisian LM. . 1997 J. Natl. Cancer Inst. 89: 1260–1270.

  • Culty M, Miyake K, Kincade PW, Sikorski E, Butcher EC and Underhill C. . 1990 J. Cell Biol. 111: 2765–2774.

  • Felgner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M, Northrop JP, Ringold GM and Danielsen M. . 1987 Proc. Natl. Acad. Sci. USA 84: 7413–7417.

  • Friedl P, Maaser K, Klein CE, Niggemann B, Krohne G and Zanker KS. . 1997 Cancer Res. 57: 2061–2070.

  • Goebeler M, Kaufmann D, Brocker EB and Klein CE. . 1996 J. Cell Sci. 109: 1957–1964.

  • Goldstein LA, Zhou DF, Picker LJ, Minty CN, Bargatze RF, Ding JF and Butcher EC. . 1989 Cell 56: 1063–1072.

    Article  CAS  Google Scholar 

  • Günthert AR, Sträter J, von Reyher U, Henne C, Joos S, Koretz K, Moldenhauer G, Krammer PH and Moller P. . 1996 J. Cell Biol. 134: 1089–1096.

  • Günthert U, Hofmann M, Rudy W, Reber S, Zöller M, Haussmann I, Matzku S, Wenzel A, Ponta H and Herrlich P. . 1991 Cell 65: 13–24.

    Article  Google Scholar 

  • Hirao M, Sato N, Kondo T, Yonemura S, Monden M, Sasaki T, Takai Y, Tsukita S and Tsukita S. . 1996 J. Cell Biol. 135: 37–51.

  • Hooper NM, Karran EH and Turner AJ. . 1997 Biochem. J. 321: 265–279.

    Article  CAS  Google Scholar 

  • Isacke CM. . 1994 J. Cell Sci. 107: 2353–2359.

  • Iwamura T, Caffrey TC, Kitamura N, Yamanari H, Setoguchi T and Hollingsworth MA. . 1997 Cancer Res. 57: 1206–1212.

  • Jackson DG, Buckley J and Bell JI. . 1992 J. Biol. Chem. 267: 4732–4739.

  • Katoh S, Zheng Z, Oritani K, Shimozato T and Kincade PW. . 1995 J. Exp. Med. 182: 419–429.

  • Lauffenburger DA and Horwitz AF. . 1996 Cell 84: 359–369.

    Article  CAS  Google Scholar 

  • Lesley J, English N, Perschl A, Gregoroff J and Hyman R. . 1995 J. Exp. Med. 182: 431–437.

  • Matsui T, Maeda M, Doi Y, Yonemura S, Amano M, Kaibuchi K, Tsukita S and Tsukita S. . 1998 J. Cell Biol. 140: 647–657.

  • Matsumura Y and Tarin D. . 1992 Lancet 340: 1053–1058.

  • Okada H, Yoshida J, Sokabe M, Wakabayashi T and Hagiwara M. . 1996 Int. J. Cancer 66: 255–260.

    Article  CAS  Google Scholar 

  • Okamoto I, Morisaki T, Sasaki J, Miyake H, Matsumoto M, Suga M, Ando M and Saya H. . 1998 J. Natl. Cancer Inst. 90: 307–315.

  • Palecek SP, Loftus JC, Ginsberg MH, Lauffenburger DA and Horwitz AF. . 1997 Nature 385: 537–540.

    Article  CAS  Google Scholar 

  • Puente XS, Pendas AM, Llano E, Velasco G and Lopez-Otin C. . 1996 Cancer Res. 56: 944–949.

  • Pure E, Camp RL, Peritt D, Panettieri RAJ, Lazaar AL and Nayak S. . 1995 J. Exp. Med. 181: 55–62.

  • Sasaki JI, Tanabe KK, Takahashi K, Okamoto I, Fujimoto H, Matsumoto M, Suga M, Ando M and Saya H. . 1998 Int. J. Oncol. 12: 525–533.

  • Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E and Seiki M. . 1994 Nature 370: 61–65.

    Article  CAS  Google Scholar 

  • Screaton GR, Bell MV, Jackson DG, Cornelis FB, Gerth U, Bell JI. . 1992 Proc. Natl. Acad. Sci. USA 89: 12160–12164.

  • Sheng Y, Yoshimura M, Inoue S, Oritani K, Nishiura T, Yoshida H, Ogawa M, Okajima Y, Matsuzawa Y and Taniguchi N. . 1997 Int. J. Cancer 73: 850–858.

    Article  CAS  Google Scholar 

  • Sleeman J, Rudy W, Hofmann M, Moll J, Herrlich P and Ponta H. . 1996 J. Cell Biol. 135: 1139–1150.

  • Stamenkovic I, Aruffo A, Amiot M and Seed B. . 1991 EMBO J. 10: 343–348.

  • Sy MS, Guo YJ and Stamenkovic I. . 1991 J. Exp. Med. 174: 859–866.

  • Takahashi K, Sasaki T, Mammoto A, Takaishi K, Kameyama T, Tsukita S and Takai Y. . 1997 J. Biol. Chem. 272: 23371–23375.

    Article  CAS  Google Scholar 

  • Takahashi K, Stamenkovic I, Cutler M, Saya H and Tanabe KK. . 1995 Oncogene 11: 2223–2232.

  • Takino T, Sato H, Shinagawa A and Seiki M. . 1995 J. Biol. Chem. 270: 23013–23020.

    Article  CAS  Google Scholar 

  • Talbot DC and Brown PD. . 1996 Eur. J. Cancer. 32A: 2528–2533.

  • Tanabe KK, Ellis LM and Saya H. . 1993a Lancet 341: 725–726.

  • Tanabe KK, Nishi T and Saya H. . 1993b Mol. Carcinog. 7: 212–220.

    Article  CAS  Google Scholar 

  • Thomas L, Byers HR, Vink J and Stamenkovic I. . 1992 J. Cell Biol. 118: 971–977.

  • Toyama-Sorimachi N, Kitamura F, Habuchi H, Tobita Y, Kimata K and Miyasaka M. . 1997 J. Biol. Chem. 272: 26714–26719.

    Article  CAS  Google Scholar 

  • Tsukita S, Oishi K, Sato N, Sagara J, Kawai A and Tsukita S. . 1994 J. Cell Biol. 126: 391–401.

  • Walcheck B, Kahn J, Fisher JM, Wang BB, Fisk RS, Payan DG, Feehan C, Betageri R, Darlak K, Spatola AF and Kishimoto TK. . 1996 Nature 380: 720–723.

    Article  CAS  Google Scholar 

  • Werb Z. . 1997 Cell 91: 439–442.

    Article  CAS  Google Scholar 

  • Will H and Hinzmann B. . 1995 Eur. J. Biochem. 231: 602–608.

Download references

Acknowledgements

We are grateful to Dr Akira Kikuchi for pBJ-Myc expression plasmids; and Drs Kenneth K Tanabe and Kazuhisa Takahashi for CD44s and CD44v8-10 expression plasmids; and Drs Kozo Kaibuchi and Mutsuki Amano for their contributions. We wish to thank Takako Arino for secretarial assistance and Dr Jon K Moon for editorial assistance. This work was supported in part by a grant from the Ministry of Health and Welfare, Japan and by a grant from the Ministry of Education, Science and Culture, Japan.

Author information

Authors and Affiliations

  1. Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto, 860-0811, Japan

    Isamu Okamoto, Yoshiaki Kawano, Hiromasa Tsuiki, Mitsuyoshi Nakao & Hideyuki Saya

  2. First Department of Internal Medicine, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto, 860-0811, Japan

    Isamu Okamoto, Ji-ichiro Sasaki, Mitsuhiro Matsumoto, Moritaka Suga & Masayuki Ando

  3. Oncology Research, Novartis Pharma. KK, Takarazuka, 665-0042, Japan

    Motowo Nakajima

Authors
  1. Isamu Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshiaki Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiromasa Tsuiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ji-ichiro Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mitsuyoshi Nakao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mitsuhiro Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Moritaka Suga
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masayuki Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Motowo Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hideyuki Saya
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okamoto, I., Kawano, Y., Tsuiki, H. et al. CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration. Oncogene 18, 1435–1446 (1999). https://doi.org/10.1038/sj.onc.1202447

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202447

Keywords

This article is cited by

Search

Advanced search

Quick links