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:

Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44

Oncogene volume 22, pages 1511–1516 (2003)Cite this article

Abstract

CD44 is the major adhesion molecule for the extracellular matrix components and is implicated in a wide variety of physiological and pathological processes including the regulation of tumor cell growth and metastasis. Our previous studies have shown that CD44 undergoes sequential proteolytic cleavages in the extracellular and transmembrane domains and the cleavage product derived from CD44 intramembranous cleavage acts as a signal transduction molecule. However, the underlying mechanism of the intramembranous cleavage of CD44 remains to be elucidated. In the present study, we report for the first time that CD44 is a substrate of the presenilin (PS)-dependent γ-secretase. We demonstrate that the intramembranous cleavage of CD44 induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment or mechanical scraping is blocked by γ-secretase inhibitors in U251MG cells and that this cleavage is also inhibited in PS-deficient mouse embryonic fibroblasts. Furthermore, we showed that PS1 is redistributed to ruffling areas of the plasma membrane similarly to CD44 after TPA treatment, supporting our biochemical observation that PS1 is involved in the intramembranous cleavage of CD44. Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/γ-secretase activity in the functional regulation of adhesion molecules.

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 1
Figure 2
Figure 3

Similar content being viewed by others

References

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

  • Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK and Rosenfeld MG . (2002). Cell, 110, 55–67.

  • Cao X and Sudhof T.C . (2001). Science, 293, 115–120

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

  • De Strooper B and Annaert W . (2001). Nat. Cell Biol., 3, E221–E225.

  • De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A and Kopan R . (1999). Nature, 398, 518–522.

  • De Strooper B, Beullens M, Contreras B, Levesque L, Craessaerts K, Cordell B, Moechars D, Bollen M, Fraser P, George-Hyslop PS and Van Leuven F . (1997). J. Biol. Chem., 272, 3590–3598.

  • Egeblad M and Werb Z . (2002). Nat. Rev. Cancer, 2, 161–174.

  • Esler WP and Wolfe MS . (2001). Science, 293, 1449–1454.

  • Evin G, Cappai R, Li QX, Culvenor JG, Small DH, Beyreuther K and Masters, C.L . (1995). Biochemistry, 34, 14185–14192.

  • Gunthert U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, Matzku S, Wenzel A, Ponta H and Herrlich P . (1991). Cell, 65, 13–24.

  • Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, Umans L, Schrijvers V, Checler F, Vanderstichele H, Baekelandt V, Dressel R, Cupers P, Huylebroeck D, Zwijsen A, Van Leuven F and De Strooper B . (1999). Proc. Natl. Acad. Sci. USA, 96, 11872–11877.

  • Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L and De Strooper B . (2000). Nat. Cell Biol., 2, 461–462.

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

  • Ito K, Okamoto I, Araki N, Kawano Y, Nakao M, Fujiyama S, Tomita K, Mimori T and Saya H . (1999). Oncogene, 18, 7080–7090.

  • Kaether C, Lammich S, Edbauer D, Ertl M, Rietdorf J, Capell A, Steiner H and Haass C . (2002). J. Cell Biol., 158, 551–561.

  • Kawano Y, Okamoto I, Murakami D, Itoh H, Yoshida M, Ueda S and Saya H . (2000). J. Biol. Chem., 275, 29628–29635.

  • Lee HJ, Jung KM, Huang YZ, Bennett LB, Lee JS, Mei L and Kim TW . (2002). J. Biol. Chem., 277, 6318–6323.

  • Lesley J and Hyman R . (1998). Front. Biosci., 3, D616–D630.

  • Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD and Wang K et al. (1995). Science, 269, 973–977.

  • Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, Wisniewski T and Robakis NK . (2002). EMBO J., 21, 1948–1956.

  • May P, Reddy YK and Herz J . (2002). J. Biol. Chem., 277, 18736–18743.

  • Ni CY, Murphy MP, Golde TE and Carpenter G . (2001). Science, 294, 2179–2181.

  • Noe V, Fingleton B, Jacobs K, Crawford HC, Vermeulen S, Steelant W, Bruyneel E, Matrisian LM and Mareel M . (2001). J. Cell Sci., 114, 111–118.

  • Okamoto I, Kawano Y, Matsumoto M, Suga M, Kaibuchi K, Ando M and Saya H . (1999a). J. Biol. Chem., 274, 25525–25534.

  • Okamoto I, Kawano Y, Murakami D, Sasayama T, Araki N, Miki T, Wong AJ and Saya H . (2001). J. Cell Biol., 155, 755–762.

  • Okamoto I, Kawano Y, Tsuiki H, Sasaki J, Nakao M, Matsumoto M, Suga M, Ando M, Nakajima M and Saya H . (1999b). Oncogene, 18, 1435–1446.

  • Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, Mar L, Sorbl S, Nacmias B, Piacentini S, Amaducci L, Chumakov I, Cohen D, Lannfelt L, Fraser PE, Rommens JM and St George-Hyslop PH. (1995). Nature, 376, 775–778.

  • Sadot E, Simcha I, Shtutman M, Ben-Ze'ev A and Geiger B . (1998). Proc. Natl. Acad. Sci. USA, 95, 15339–15344.

  • Seiffert D, Bradley JD, Rominger CM, Rominger DH, Yang F, Meredith Jr JE, Wang Q, Roach AH, Thompson LA, Spitz SM, Higaki JN, Prakash SR, Combs AP, Copeland RA, Arneric SP, Hartig PR, Robertson DW, Cordell B, Stern AM, Olson RE and Zaczek R . (2000). J. Biol. Chem., 275, 34086–34091.

  • Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T, Hunt P, Nadin A, Smith AL, Stevenson G and Castro JL . (2000). Biochemistry, 39, 8698–8704.

  • Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HAR, Haines JL, Pericak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM and St George-Hyslop PH . (1995). Nature, 375, 754–760.

  • Struhl G, Adachi A . (2000). Mol. Cell, 6, 625–636.

  • Weber GF, Bronson RT, Ilagan J, Cantor H, Schmits R and Mak TW . (2002). Cancer Res., 62, 2281–2286.

Download references

Acknowledgements

We are grateful to Dr Yasuo Ihara (University of Tokyo) for providing antibody C4; Dr WG Stetler-Stevenson for providing BB94; and members of the Gene Technology Center in Kumamoto University for their important contributions to the experiments. We wish to thank Yoshimi Fukushima for secretarial assistance. This work was supported by a grant for cancer research from the Ministry of Education, Science and Culture of Japan (HS) and ‘Research for the Future’ program of the Japan Society for the Promotion of Science (HS).

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

    Daizo Murakami, Osamu Nagano, Yoshiaki Kawano & Hideyuki Saya

  2. Department of Otolaryngology-Head and Neck Surgery, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

    Daizo Murakami & Eiji Yumoto

  3. First Department of Internal Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

    Isamu Okamoto

  4. Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Taisuke Tomita & Takeshi Iwatsubo

  5. Center for Human Genetics, KU Leuven and Flanders Interuniversity Institute for Biotechnology (VIB), Herestraat 49, Leuven, 3000, Belgium

    Bart De Strooper

Authors
  1. Daizo Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isamu Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Osamu Nagano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshiaki Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Taisuke Tomita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takeshi Iwatsubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bart De Strooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eiji Yumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hideyuki Saya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideyuki Saya.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Murakami, D., Okamoto, I., Nagano, O. et al. Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44. Oncogene 22, 1511–1516 (2003). https://doi.org/10.1038/sj.onc.1206298

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206298

Keywords

This article is cited by

Search

Advanced search

Quick links