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α6β1 integrin induces proteasome-mediated cleavage of erbB2 in breast cancer cells

Oncogene volume 22, pages 831–839 (2003)Cite this article

Abstract

ErbB2 and α6 integrin have been implicated in malignancy of breast cancer cells. Here we have determined the influence of α6β1 integrin on erbB2 signaling in anchorage-independent growth, using MDA-MB435 breast cancer cells. Firstly, we transfected the cells with erbB2 cDNA, and isolated cells with high or low levels of α6β1 integrin by cell sorting (α6H-ErbB and α6L-ErbB). We found that an erbB ligand, heregulin β1, enhanced growth activity of α6L-ErbB cells, but not α6H-ErbB cells. Secondly, we established cells expressing a β4 integrin deletion mutant (β4-Δcyt), which selectively inhibited α6β1 integrin expression and adhesion to laminin-1. Again, heregulin β1 enhanced the growth of erbB2 cDNA-transfected β4-Δcyt cells, but not mock cells. Western blot analysis revealed that heregulin β1 stimulated phosphorylation of Akt and its downstream molecules, GSK3β and p70S6kinase, and that the extent of phosphorylation was greater in ErbB2/β4-Δcyt cells than ErbB2/mock cells. Furthermore, we found that the erbB2 cytoplasmic domain was truncated in ErbB2/mock cells, which was independent of ligand stimulation and adhesion, and was suppressed by proteasome inhibitors. These results suggest that α6β1 integrin inhibits erbB2 signals by inducing proteasome-dependent proteolytic cleavage of the erbB2 cytoplasmic domain, and may thereby contribute to the regulation of tumor growth.

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References

  • Adelsman MA, McCarthy JB and Shimizu Y . (1999). Mol. Biol. Cell, 10, 2861–2878.

  • Aguilar Z, Akita RW, Finn RS, Ramos BL, Pegram MD, Kabbinavar FF, Pietras RJ, Pisacane P, Sliwkowski MX and Slamon DJ . (1999). Oncogene, 18, 6050–6062.

  • Amundadottir LT and Leder P . (1998). Oncogene, 16, 737–746.

  • Bachelder RE, Ribick MJ, Marchetti A, Falcioni R, Soddu S, Davis KR and Mercurio AM . (1999). J. Cell Biol., 147, 1063–1072.

  • Bao W, Thullberg M, Zhang H, Onischenko A and Stromblad S . (2002). Mol. Cell Biol., 22, 4587–4597.

  • Baron V and Schwartz M . (2000). J. Biol. Chem., 275, 39318–39123.

  • Bialkowska K, Kulkarni S, Du X, Goll DE, Saido TC and Fox JE . (2000). J. Cell Biol., 151, 685–696.

  • Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Stetler-Stevenson WG, Quigley JP and Cheresh DA . (1996). Cell, 85, 683–693.

  • Campiglio M, Tagliabue E, Srinivas U, Pellegrini R, Martignone S, Menard S, Colnaghi MI, Lombardi L and Marchisio PC . (1994). J. Cell Biochem., 55, 409–418.

  • Carrano AC and Pagano M . (2001). J. Cell Biol., 153, 1381–1390.

  • Christianson TA, Doherty JK, Lin YJ, Ramsey EE, Holmes R, Keenan EJ and Clinton GM . (1998). Cancer Res., 58, 5123–5129.

  • Clarke AS, Lotz MM, Chao C and Mercurio AM . (1995). J. Biol. Chem., 270, 22673–22676.

  • Codony-Servat J, Albanell J, Lopez-Talavera JC, Arribas J and Baselga J . (1999). Cancer Res., 59, 1196–1201.

  • Danilenko DM, Ring BD, Lu JZ, Tarpley JE, Chang D, Liu N, Wen D and Pierce GF . (1995). J. Clin. Invest., 95, 842–851.

  • Falcioni R, Antonini A, Nistico P, Di Stefano S, Crescenzi M, Natali PG and Sacchi A . (1997). Exp. Cell Res., 236, 76–85.

  • Friedrichs K, Ruiz P, Franke F, Gille I, Terpe HJ and Imhof BA . (1995). Cancer Res., 55, 901–906.

  • Gambaletta D, Marchetti A, Benedetti L, Mercurio AM, Sacchi A and Falcioni R . (2000). J. Biol. Chem., 275, 10604–10610.

  • Hammond DE, Urbe S, Vande Woude GF and Clague MJ . (2001). Oncogene, 20, 2761–2770.

  • Hijazi MM, Thompson EW, Tang C, Coopman P, Torri JA, Yang D, Mueller SC and Lupu R . (2000). Int. J. Oncol., 17, 629–641.

  • Hintermann E, Bilban M, Sharabi A and Quaranta V . (2001). J. Cell Biol., 153, 465–478.

  • Jeffers M, Taylor GA, Weidner KM, Omura S and Vande Woude GF . (1997). Mol. Cell Biol., 17, 799–808.

  • Koukoulis GK, Virtanen I, Korhonen M, Laitinen L, Quaranta V and Gould VE . (1991). Am. J. Pathol., 39, 787–799.

  • Kozlova NI, Morozevich GE, Chubukina AN and Berman AE . (2001). Oncogene, 20, 4710–4717.

  • Krane IM and Leder P . (1996). Oncogene, 12, 1781–1788.

  • Lane HA, Beuvink I, Motoyama AB, Daly JM, Neve RM and Hynes NE . (2000). Mol. Cell Biol., 20, 3210–3223.

  • Lee YJ and Streuli CH . (1999). J. Biol. Chem., 274, 22401–22408.

  • Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, Lavi S, Iwai K, Reiss Y, Ciechanover A, Lipkowitz S and Yarden Y . (1999). Mol. Cell, 4, 1029–1040.

  • Lichtner RB, Kaufmann AM, Kittmann A, Rohde-Schulz B, Walter J, Williams L, Ullrich A, Schirrmacher V and Khazaie K . (1995). Oncogene, 10, 1823–1832.

  • Lin YZ and Clinton GM . (1991). Oncogene, 6, 639–643.

  • Longva KE, Blystad FD, Stang E, Larsen AM, Johannessen LE and Madshus IH . (2002). J. Cell Biol., 156, 843–854.

  • Manenti S, Delmas C and Darbon JM . (2002). Biochem. Biophys. Res. Commun., 294, 976–980.

  • Meng F and Lowell CA . (1998). EMBO J., 17, 4391–4403.

  • Miyamoto S, Teramoto H, Gutkind JS and Yamada KM . (1996). J. Cell Biol., 135, 1633–1642.

  • Mori S, Tanaka K, Omura S and Saito Y . (1995). J. Biol. Chem., 270, 29447–29452.

  • Moro L, Venturino M, Bozzo C, Silengo L, Altruda F, Beguinot L, Tarone G and Defilippi P . (1998). EMBO J., 17, 6622–6632.

  • Mukhopadhyay R, Theriault RL and Price JE . (1999). Clin. Exp. Metastasis, 17, 325–332.

  • Natali PG, Nicotra MR, Botti C, Mottolese M, Bigotti A and Segatto O . (1992). Br. J. Cancer, 66, 318–322.

  • Neve RM, Sutterluty H, Pullen N, Lane HA, Daly JM, Krek W and Hynes NE . (2000). Oncogene, 19, 1647–1656.

  • O'Connor KL, Shaw LM and Mercurio AM . (1998). J. Cell Biol., 143, 1749–1760.

  • Ojaniemi M, Martin SS, Dolfi F, Olefsky JM and Vuori K . (1997). J. Biol. Chem., 272, 3780–3787.

  • Perez-Tenorio G and Stal O . (2002). Br. J. Cancer, 86, 540–545.

  • Pignatelli M, Hanby AM and Stamp GW . (1991). J. Pathol., 165, 25–32.

  • Plath T, Detjen K, Welzel M, von Marschall Z, Murphy D, Schirner M, Wiedenmann B and Rosewicz S, (2000). J. Cell Biol., 150, 467–478.

  • Pupa SM, Menard S, Morelli D, Pozzi B, De Palo G and Colnaghi MI . (1993). Oncogene, 8, 2917–2923.

  • Renshaw MW, Price LS and Schwartz MA . (1999). J. Cell Biol., 147, 611–618.

  • Rock KL, Gramm C, Rothstein L, Clark K, Stein R, Dick L, Hwang D and Goldberg AL . (1994). Cell, 78, 761–771.

  • Schneller M, Vuori K and Ruoslahti E . (1997). EMBO J., 16, 5600–5607.

  • Shimizu H, Koyama N, Asada M and Yoshimatsu K . (2002). Int. J. Oncol., 21, 1073–1079.

  • Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G and Bussolino F . (1999). EMBO J., 18, 882–892.

  • Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM and Cheresh DA . (2001). J. Cell Biol., 155, 459–470.

  • Sun H, Santoro SA and Zutter MM . (1998). Cancer Res., 58, 2224–2233.

  • Tagliabue E, Ardini E, Pellegrini R, Campiglio M, Bufalino R, Jeschke M, Groner B, Colnaghi MI and Menard S . (1996). Br. J. Cancer, 74, 1427–1433.

  • Tagliabue E, Ghirelli C, Squicciarini P, Aiello P, Colnaghi MI and Menard S . (1998). Clin. Cancer. Res., 4, 407–410.

  • Tan M, Yao J and Yu D . (1997). Cancer Res., 57, 1199–1205.

  • Trusolino L, Bertotti A and Comoglio PM . (2001). Cell, 107, 643–654.

  • Tzahar E and Yarden Y . (1998). Biochim. Biophys. Acta., 1377, M25–M37.

  • Vafa A, Zhang Y, Sikes RA and Marengo SR . (1998). Int. J. Oncol., 13, 1191–1197.

  • Varner JA, Emerson DA and Juliano RL . (1995). Mol Biol Cell, 6, 725–740.

  • Vogelmann R, Kreuser ED, Adler G and Lutz MP . (1999). Int. J. Cancer., 80, 791–795.

  • Wang F, Weaver VM, Petersen OW, Larabell CA, Dedhar S, Briand P, Lupu R and Bissell MJ . (1998). Proc. Natl. Acad. Sci. USA, 95, 14821–14826.

  • Wewer UM, Shaw LM, Albrechtsen R and Mercurio AM . (1997). Am. J. Pathol., 151, 1191–1198.

  • Xu FJ, Stack S, Boyer C, O'Briant K, Whitaker R, Mills GB, Yu YH and Bast Jr RC . (1997). Clin. Cancer Res., 3, 1629–1634.

  • Yarwood SJ and Woodgett JR . (2001). Proc. Natl. Acad. Sci. USA, 98, 4472–4477.

  • Yebra M, Goretzki L, Pfeifer M and Mueller BM . (1999). Exp. Cell Res., 250, 231–240.

  • Yu D, Liu B, Tan M, Li J, Wang SS and Hung MC . (1996). Oncogene, 13, 1359–1365.

  • Yu X, Miyamoto S and Mekada E . (2000). J. Cell Sci., 113, 2139–2147.

  • Zhou BP, Hu MC, Miller SA, Yu Z, Xia W, Lin SY and Hung MC . (2000). J. Biol. Chem., 275, 8027–8031.

  • Zutter MM, Santoro SA, Staatz WD and Tsung YL . (1995). Proc. Natl. Acad. Sci. USA, 92, 7411–7415.

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  1. Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, 300-2635, Ibaraki, Japan

    Hajime Shimizu, Takashi Seiki, Makoto Asada, Kentaro Yoshimatsu & Noriyuki Koyama

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  1. Hajime Shimizu
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  2. Takashi Seiki
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Correspondence to Hajime Shimizu.

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Shimizu, H., Seiki, T., Asada, M. et al. α6β1 integrin induces proteasome-mediated cleavage of erbB2 in breast cancer cells. Oncogene 22, 831–839 (2003). https://doi.org/10.1038/sj.onc.1206203

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