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:

Tetraspanin CD81 is linked to ERK/MAPKinase signaling by Shc in liver tumor cells

Oncogene volume 23, pages 1566–1574 (2004)Cite this article

Abstract

Tetraspanins is a large family of membrane proteins that are implicated in cell proliferation, differentiation and tumor invasion. Specifically, the tetraspanin CD81 has been involved in cell proliferation but the mechanism is unknown. Here, we show that CD81 clustering stimulates ERK/MAPKinase activity and tyrosine phosphorylation of the adapter protein Shc in Huh7 cancer cells. In addition, overexpression of CD81 in HepG2 cells, NIH3T3 cells, and murine fibroblasts GD25 lacking the β1 family of integrins induces cell proliferation and ERK/MAPKinase activation. Linked with this event, we observed an increase in CD81-associated type II phosphatidylinositol 4-kinase activity. A mutant in the PTB domain of Shc failed to interact with phosphoinositides and localize to the plasma membrane thus blocking CD81-induced ERK/MAPKinase activation. Therefore, we conclude that CD81 stimulates synthesis of phosphoinositides with the recruitment of Shc to the plasma membrane via PTB domain, and this sequence of events induces activation of ERK/MAPKinase. These findings define a novel mechanism of ERK/MAPKinase activation and tumor cell proliferation.

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

Similar content being viewed by others

Abbreviations

PtdIns:

phosphatidylinositol

PtdIns 4-kinase:

phosphatidylinositol 4-kinase

PH:

pleckstrin homology

PTB:

phosphotyrosine binding

GST:

glutathione S-transferase

PAGE:

polyacrylamide gel electrophoresis

PIP:

phosphatidylinositol monophosphate

ERK:

extracellular-regulated kinase

References

  • Berditchevski F . (2001). J. Cell. Sci., 114, 4143–4151.

  • Berditchevski F, Zutter MM and Hemler ME . (1996). Mol. Biol. Cell, 7, 193–207.

  • Claas C, Stipp CS and Hemler ME . (2001). J. Biol. Chem., 276, 7974–7984.

  • Fassler R, Pfaff M, Murphy J, Noegel AA, Johansson S, Timpl R and Albrecht R . (1995). J. Cell Biol., 128, 979–988.

  • Fruman DA, Meyers RE and Cantley LC . (1998). Annu. Rev. Biochem., 67, 481–507.

  • Hemler M E . (2001). J. Cell Biol., 155, 1103–1107.

  • Kurzchalia TV and Parton RG . (1999). Curr. Opin. Cell Biol., 11, 424–431.

  • Lemmon MA and Ferguson KM . (2000). Biochem. J., 350, 1–18.

  • Levy S, Nguyen VQ, Andria ML and Takahashi S . (1991). J. Biol. Chem., 266, 14597–14602.

  • Levy S, Todd SC and Maecker HT . (1998). Annu. Rev. Immunol., 16, 89–109.

  • Maecker HT, Do MS and Levy S . (1998). Proc. Natl. Acad. Sci. USA, 95, 2458–2462.

  • Martin TFJ . (1998). Annu. Rev. Cell Dev. Biol., 14, 231–264.

  • Mazzocca A, Carloni V, Cappadona Sciammetta S, Cordella C, Pantaleo P, Caldini A, Gentilini P and Pinzani M . (2002). J. Hepatol., 37, 322–330.

  • Melkonian KA, Ostermeyer AG, Chen JZ, Roth MG and Brown DA . (1999). J. Biol. Chem., 274, 3910–3917.

  • Minogue S, Anderson JS, Waugh MG, dos Santos M, Corless S, Cramer R and Hsuan JJ . (2001). J. Biol. Chem., 276, 16635–16640.

  • Miyazaki T, Muller U and Campbell KS . (1997). EMBO J., 16, 4217–4225.

  • Oren R, Takahashi S, Doss C, Levy R and Levy S . (1990). Mol. Cell. Biol., 10, 4007–4015.

  • Owens DM and Watt FM . (2001). Cancer Res., 61, 5248–5254.

  • Rameh LE, Arvidsson A, Carraway KL, Couvillon AD, Rathbun G, Crompton A, Van Renterghem B, Czech MP, Ravichandran KS, Burakoff SJ, Wang DS, Chen CS and Cantley LC . (1997). J. Biol. Chem., 272, 22059–22066.

  • Raucher D, Stauffer T, Chen W, Shen K, Guo S, York JD, Sheetz MP and Meyer T . (2000). Cell, 100, 221–228.

  • Ravichandran KS . (2001). Oncogene, 20, 6322–6330.

  • Ravichandran KS, Ming-Ming Z, Pratt JC, Harlan JE, Walk SF, Fesik SW and Burakoff SJ . (1997). Mol. Cell. Biol., 17, 5540–5549.

  • Schick MR and Levy S . (1993). J. Immunol., 151, 4090–4097.

  • Serru V, Le Naour F, Billard M, Azorsa DO, Lanza F, Boucheix C and Rubinstein E . (1999). Biochem. J., 340, 103–111.

  • Silvie O, Rubinstein E, Franetich JF, Prenant M, Belnoue E, Renia L, Hannoun L, Eling W, Levy S, Boucheix C and Mazier D . (2003). Nat. Med., 9, 93–96.

  • Simons K and Toomre D . (2000). Nat. Rev., 1, 31–39.

  • Tanaka M, Gupta R and Mayer BJ . (1995). Mol. Cell. Biol., 15, 6829–6837.

  • Wang YD, De Vos J, Jourdan M, Couderc G, Rossi JF and Klein . (2002). Oncogene, 21, 2584–2592.

  • Wei Yong Jie, Sun HQ, Yamamoto M, Wlodarski P, Kunii K, Martinez M, Barylko B, Albanesi JP and Yin HL . (2002). J. Biol. Chem., 277, 46586–46593.

  • Wennerberg K, Armulik A, Sakai T, Karlsson M, Fassler R, Schaefer EM, Mosher DF and Johansson S . (2000). Mol. Cell. Biol., 20, 5758–5765.

  • Yauch RL, Berditchevski F, Harler MB, Reichner RL and Hemler ME . (1998). Mol. Biol. Cell., 9, 2751–2765.

  • Yauch RL and Hemler ME . (2000). Biochem. J., 351, 629–637.

  • Zhang W and Samelson LE . (2000). Semin Immunol., 12, 35–41.

  • Zhou MM, Ravichandran KS, Olejniczak ET, Petros AM, Meadows RP, Sattler M, Harlan JE, Wade WS, Burakoff SJ and Fesik SW . (1995). Nature, 378, 584–592.

Download references

Acknowledgements

We thank Piero Pileri for generously providing expression plasmid for CD81 and Reinhard Fassler for GD25 cell line. We also thank Fedor Berditchevski for providing antibodies. This work was supported by grants from Ministero Italiano dell'Università e della Ricerca Scientifica e Tecnologica (MIUR)

Author information

Author notes

  1. Vinicio Carloni and Antonio Mazzocca: These authors contributed equally to this work

Authors and Affiliations

  1. Dipartimento di Medicina Interna, Università di Firenze, Viale Morgagni, 85, Firenze, I-50134, Italy

    Vinicio Carloni & Antonio Mazzocca

  2. Beirne Carter Center for Immunology Research and the Department of Microbiology, University of Virginia, Charlottesville, VA, USA

    Kodimangalam S Ravichandran

Authors
  1. Vinicio Carloni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Mazzocca
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kodimangalam S Ravichandran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vinicio Carloni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carloni, V., Mazzocca, A. & Ravichandran, K. Tetraspanin CD81 is linked to ERK/MAPKinase signaling by Shc in liver tumor cells. Oncogene 23, 1566–1574 (2004). https://doi.org/10.1038/sj.onc.1207287

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207287

Keywords

This article is cited by

Search

Advanced search

Quick links