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.

  • Review
  • Published:

Nuclear trafficking of the epidermal growth factor receptor family membrane proteins

Oncogene volume 29, pages 3997–4006 (2010)Cite this article

Subjects

Abstract

Multiple membrane-bound receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR) and ErbB-2, have been reported to be localized in the nucleus, where emerging evidence suggests that they are involved in transcriptional regulation, cell proliferation, DNA repair and chemo- and radio-resistance. Recent studies have shown that endocytosis and endosomal sorting are involved in the nuclear transport of cell surface RTKs. However, the detailed mechanism by which the full-length receptors embedded in the endosomal membrane travel all the way from the cell surface to the early endosomes and pass through the nuclear pore complexes is unknown. This important area has been overlooked for decades, which has hindered progress in our understanding of nuclear RTKs’ functions. Here, we discuss the putative mechanisms by which EGFR family RTKs are shuttled into the nucleus. Understanding the trafficking mechanisms as to how RTKs are transported from the cell surface to the nucleus will significantly contribute to understanding the functions of the nuclear RTKs.

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

Similar content being viewed by others

References

  • Adam RM, Danciu T, McLellan DL, Borer JG, Lin J, Zurakowski D et al (2003). A nuclear form of the heparin-binding epidermal growth factor-like growth factor precursor is a feature of aggressive transitional cell carcinoma. Cancer Res 63: 484–490.

    CAS  PubMed  Google Scholar 

  • Arasada RR, Carpenter G . (2005). Secretase-dependent tyrosine phosphorylation of Mdm2 by the ErbB-4 intracellular domain fragment. J Biol Chem 280: 30783–30787.

    CAS  PubMed  Google Scholar 

  • Bailey KE, Costantini DL, Cai Z, Scollard DA, Chen Z, Reilly RM et al. (2007). Epidermal growth factor receptor inhibition modulates the nuclear localization and cytotoxicity of the Auger electron emitting radiopharmaceutical 111In-DTPA human epidermal growth factor. J Nucl Med 48: 1562–1570.

    CAS  PubMed  Google Scholar 

  • Baldys A, Raymond JR . (2009). Critical role of ESCRT machinery in EGFR recycling. Biochemistry 48: 9321–9323.

    CAS  PubMed  Google Scholar 

  • Bao J, Wolpowitz D, Role LW, Talmage DA . (2003). Back signaling by the Nrg-1 intracellular domain. J Cell Biol 161: 1133–1141.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bryant DM, Stow JL . (2005). Nuclear translocation of cell-surface receptors: lessons from fibroblast growth factor. Traffic 6: 947–954.

    CAS  PubMed  Google Scholar 

  • Bueter W, Dammann O, Zscheppang K, Korenbaum E, Dammann CE . (2006). ErbB receptors in fetal endothelium—a potential linkage point for inflammation-associated neonatal disorders. Cytokine 36: 267–275.

    CAS  PubMed  Google Scholar 

  • Carpenter G . (2003). Nuclear localization and possible functions of receptor tyrosine kinases. Curr opin cell biol 15: 143–148.

    CAS  PubMed  Google Scholar 

  • Carpenter G, Liao HJ . (2009). Trafficking of receptor tyrosine kinases to the nucleus. Exp Cell Res 315: 1556–1566.

    CAS  PubMed  Google Scholar 

  • Ceresa BP . (2006). Regulation of EGFR endocytic trafficking by rab proteins. Histol Histopathol 21: 987–993.

    CAS  PubMed  Google Scholar 

  • Ceresa BP, Bahr SJ . (2006). rab7 activity affects epidermal growth factor:epidermal growth factor receptor degradation by regulating endocytic trafficking from the late endosome. J Biol Chem 281: 1099–1106.

    CAS  PubMed  Google Scholar 

  • Chen DJ, Nirodi CS . (2007). The epidermal growth factor receptor: a role in repair of radiation-induced DNA damage. Clin Cancer Res 13: 6555–6560.

    CAS  PubMed  Google Scholar 

  • Ciardiello F, Tortora G . (2008). EGFR antagonists in cancer treatment. New Eng J Med 358: 1160–1174.

    CAS  PubMed  Google Scholar 

  • Citri A, Yarden Y . (2006). EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7: 505–516.

    CAS  PubMed  Google Scholar 

  • Conner SD, Schmid SL . (2003). Regulated portals of entry into the cell. Nature 422: 37–44.

    CAS  PubMed  Google Scholar 

  • Cook A, Bono F, Jinek M, Conti E . (2007). Structural biology of nucleocytoplasmic transport. Annu Rev Biochem 76: 647–671.

    CAS  PubMed  Google Scholar 

  • Das AK, Chen BP, Story MD, Sato M, Minna JD, Chen DJ et al. (2007). Somatic mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) abrogate EGFR-mediated radioprotection in non-small cell lung carcinoma. Cancer Res 67: 5267–5274.

    CAS  PubMed  Google Scholar 

  • de la Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ et al. (2008). Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Gen develop 22: 449–462.

    CAS  Google Scholar 

  • Di Cosimo S, Baselga J . (2010). Management of breast cancer with targeted agents: importance of heterogenicity. Nat Rev Clin Oncol 7: 139–147.

    PubMed  Google Scholar 

  • Dittmann K, Mayer C, Fehrenbacher B, Schaller M, Raju U, Milas L et al. (2005a). Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J Biol Chem 280: 31182–31189.

    CAS  PubMed  Google Scholar 

  • Dittmann K, Mayer C, Rodemann HP . (2005b). Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity. Radiother Oncol 76: 157–161.

    CAS  PubMed  Google Scholar 

  • Dittmann K, Mayer C, Kehlbach R, Rodemann HP . (2008a). Radiation-induced caveolin-1 associated EGFR internalization is linked with nuclear EGFR transport and activation of DNA-PK. Mol Cancer 7: 69.

    PubMed  PubMed Central  Google Scholar 

  • Dittmann KH, Mayer C, Ohneseit PA, Raju U, Andratschke NH, Milas L et al. (2008b). Celecoxib induced tumor cell radiosensitization by inhibiting radiation induced nuclear EGFR transport and DNA-repair: a COX-2 independent mechanism. Int J Radiat Oncol Biol Phys 70: 203–212.

    CAS  PubMed  Google Scholar 

  • Doherty GJ, McMahon HT . (2009). Mechanisms of endocytosis. Annu Rev Biochem 78: 857–902.

    CAS  PubMed  Google Scholar 

  • Edwards J, Traynor P, Munro AF, Pirret CF, Dunne B, Bartlett JM . (2006). The role of HER1-HER4 and EGFRvIII in hormone-refractory prostate cancer. Clin Cancer Res 12: 123–130.

    CAS  PubMed  Google Scholar 

  • Esteva FJ, Yu D, Hung MC, Hortobagyi GN . (2010). Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat Rev Clin Oncol 7: 98–107.

    CAS  PubMed  Google Scholar 

  • Fang X, Stachowiak EK, Dunham-Ems SM, Klejbor I, Stachowiak MK . (2005). Control of CREB-binding protein signaling by nuclear fibroblast growth factor receptor-1: a novel mechanism of gene regulation. J Biol Chem 280: 28451–28462.

    CAS  PubMed  Google Scholar 

  • Gazdar AF . (2009). Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 28 (Suppl 1): S24–S31.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Giri DK, Ali-Seyed M, Li LY, Lee DF, Ling P, Bartholomeusz G et al. (2005). Endosomal transport of ErbB-2: mechanism for nuclear entry of the cell surface receptor. Mol Cell Biol 25: 11005–11018.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grant BD, Donaldson JG . (2009). Pathways and mechanisms of endocytic recycling. Nat Rev Mol Cell Biol 10: 597–608.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grasl-Kraupp B, Schausberger E, Hufnagl K, Gerner C, Low-Baselli A, Rossmanith W et al. (2002). A novel mechanism for mitogenic signaling via pro-transforming growth factor alpha within hepatocyte nuclei. Hepatology 35: 1372–1380.

    CAS  PubMed  Google Scholar 

  • Gruenberg J, Stenmark H . (2004). The biogenesis of multivesicular endosomes. Nat Rev Mol Cell Biol 5: 317–323.

    CAS  PubMed  Google Scholar 

  • Hanada N, Lo HW, Day CP, Pan Y, Nakajima Y, Hung MC . (2006). Co-regulation of B-Myb expression by E2F1 and EGF receptor. Mol Carcinog 45: 10–17.

    CAS  PubMed  Google Scholar 

  • Harel A, Forbes DJ . (2004). Importin beta: conducting a much larger cellular symphony. Mol Cell 16: 319–330.

    CAS  PubMed  Google Scholar 

  • Hieda M, Isokane M, Koizumi M, Higashi C, Tachibana T, Shudou M et al. (2008). Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane. J Cell Biol 180: 763–769.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Higashiyama S, Iwabuki H, Morimoto C, Hieda M, Inoue H, Matsushita N . (2008). Membrane-anchored growth factors, the epidermal growth factor family: beyond receptor ligands. Cancer Sci 99: 214–220.

    CAS  PubMed  Google Scholar 

  • Hoelz A, Blobel G . (2004). Cell biology: popping out of the nucleus. Nature 432: 815–816.

    CAS  PubMed  Google Scholar 

  • Hoshino M, Fukui H, Ono Y, Sekikawa A, Ichikawa K, Tomita S et al. (2007). Nuclear expression of phosphorylated EGFR is associated with poor prognosis of patients with esophageal squamous cell carcinoma. Pathobiology 74: 15–21.

    CAS  PubMed  Google Scholar 

  • Hsu SC, Hung MC . (2007). Characterization of a novel tripartite nuclear localization sequence in the EGFR family. J Biol Chem 282: 10432–10440.

    CAS  PubMed  Google Scholar 

  • Hsu SC, Miller SA, Wang Y, Hung MC . (2009). Nuclear EGFR is required for cisplatin resistance and DNA repair. Am J Transl Res 1: 249–258.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hu S, Xie Z, Onishi A, Yu X, Jiang L, Lin J et al. (2009). Profiling the human protein-DNA interactome reveals ERK2 as a transcriptional repressor of interferon signaling. Cell 139: 610–622.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang PH, Xu AM, White FM . (2009). Oncogenic EGFR signaling networks in glioma. Sci Signal 2: re6.

    PubMed  Google Scholar 

  • Hung LY, Tseng JT, Lee YC, Xia W, Wang YN, Wu ML et al. (2008). Nuclear epidermal growth factor receptor (EGFR) interacts with signal transducer and activator of transcription 5 (STAT5) in activating Aurora-A gene expression. Nucleic Acids Res 36: 4337–4351.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hynes NE, Lane HA . (2005). ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5: 341–354.

    CAS  PubMed  Google Scholar 

  • Hynes NE, MacDonald G . (2009). ErbB receptors and signaling pathways in cancer. Curr opin cell biol 21: 177–184.

    CAS  PubMed  Google Scholar 

  • Irmer D, Funk JO, Blaukat A . (2007). EGFR kinase domain mutations—functional impact and relevance for lung cancer therapy. Oncogene 26: 5693–5701.

    CAS  PubMed  Google Scholar 

  • Jans DA, Xiao CY, Lam MH . (2000). Nuclear targeting signal recognition: a key control point in nuclear transport? Bioessays 22: 532–544.

    CAS  PubMed  Google Scholar 

  • Johannes L, Popoff V . (2008). Tracing the retrograde route in protein trafficking. Cell 135: 1175–1187.

    CAS  PubMed  Google Scholar 

  • Jones FE . (2008). HER4 intracellular domain (4ICD) activity in the developing mammary gland and breast cancer. J Mammary Gland Biol Neoplasia 13: 247–258.

    PubMed  PubMed Central  Google Scholar 

  • Kim HP, Yoon YK, Kim JW, Han SW, Hur HS, Park J et al. (2009). Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2. PLoS One 4: e5933.

    PubMed  PubMed Central  Google Scholar 

  • Kim J, Jahng WJ, Di Vizio D, Lee JS, Jhaveri R, Rubin MA et al. (2007). The phosphoinositide kinase PIKfyve mediates epidermal growth factor receptor trafficking to the nucleus. Cancer Res 67: 9229–9237.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kimura H . (1993). Schwannoma-derived growth factor must be transported into the nucleus to exert its mitogenic activity. Proc Natl Acad Sci USA 90: 2165–2169.

    CAS  PubMed  PubMed Central  Google Scholar 

  • King MC, Lusk CP, Blobel G . (2006). Karyopherin-mediated import of integral inner nuclear membrane proteins. Nature 442: 1003–1007.

    CAS  PubMed  Google Scholar 

  • Klein C, Gensburger C, Freyermuth S, Nair BC, Labourdette G, Malviya AN. . (2004). A 120 kDa nuclear phospholipase Cgamma1 protein fragment is stimulated in vivo by EGF signal phosphorylating nuclear membrane EGFR. Biochemistry 43: 15873–15883.

    CAS  PubMed  Google Scholar 

  • Li C, Iida M, Dunn EF, Ghia AJ, Wheeler DL . (2009). Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene 28: 3801–3813.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liao HJ, Carpenter G . (2007). Role of the Sec61 translocon in EGF receptor trafficking to the nucleus and gene expression. Mol Biol Cell 18: 1064–1072.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lin SY, Makino K, Xia W, Matin A, Wen Y, Kwong KY et al. (2001). Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol 3: 802–808.

    CAS  PubMed  Google Scholar 

  • Linardou H, Dahabreh IJ, Bafaloukos D, Kosmidis P, Murray S . (2009). Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nat Rev 6: 352–366.

    CAS  Google Scholar 

  • Linggi B, Carpenter G . (2006). ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional repression. J Biol Chem 281: 25373–25380.

    CAS  PubMed  Google Scholar 

  • Lo HW, Hsu SC, Ali-Seyed M, Gunduz M, Xia W, Wei Y et al. (2005a). Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell 7: 575–589.

    CAS  PubMed  Google Scholar 

  • Lo HW, Xia W, Wei Y, Ali-Seyed M, Huang SF, Hung MC . (2005b). Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. Cancer Res 65: 338–348.

    CAS  PubMed  Google Scholar 

  • Lo HW, Ali-Seyed M, Wu Y, Bartholomeusz G, Hsu SC, Hung MC . (2006a). Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1. J Cell Biochem 98: 1570–1583.

    CAS  PubMed  Google Scholar 

  • Lo HW, Hsu SC, Hung MC . (2006b). EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Res Treat 95: 211–218.

    CAS  PubMed  Google Scholar 

  • Lo HW, Hung MC . (2006). Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival. Br J Cancer 94: 184–188.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lo HW, Cao X, Zhu H, Ali-Osman F . (2010). Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFR-STAT3 and EGFRvIII-STAT3 signaling axes. Mol Cancer Res 8: 232–245.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lusk CP, Blobel G, King MC . (2007). Highway to the inner nuclear membrane: rules for the road. Nat Rev Mol Cell Biol 8: 414–420.

    CAS  PubMed  Google Scholar 

  • Marti U, Burwen SJ, Wells A, Barker ME, Huling S, Feren AM et al. (1991). Localization of epidermal growth factor receptor in hepatocyte nuclei. Hepatology (Baltimore, MD) 13: 15–20.

    CAS  Google Scholar 

  • Marti U, Hug M . (1995). Acinar and cellular distribution and mRNA expression of the epidermal growth factor receptor are changed during liver regeneration. J Hepatol 23: 318–327.

    CAS  PubMed  Google Scholar 

  • Marti U, Wells A . (2000). The nuclear accumulation of a variant epidermal growth factor receptor (EGFR) lacking the transmembrane domain requires coexpression of a full-length EGFR. Mol Cell Biol Res Commun 3: 8–14.

    CAS  PubMed  Google Scholar 

  • Massie C, Mills IG . (2006). The developing role of receptors and adaptors. Nat Rev Cancer 6: 403–409.

    CAS  PubMed  Google Scholar 

  • Maxfield FR, McGraw TE . (2004). Endocytic recycling. Nat Rev Mol Cell Biol 5: 121–132.

    CAS  PubMed  Google Scholar 

  • Mayor S, Pagano RE . (2007). Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol 8: 603–612.

    CAS  PubMed  Google Scholar 

  • Miaczynska M, Christoforidis S, Giner A, Shevchenko A, Uttenweiler-Joseph S, Habermann B et al. (2004). APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell 116: 445–456.

    CAS  PubMed  Google Scholar 

  • Mills IG, Gaughan L, Robson C, Ross T, McCracken S, Kelly J et al. (2005). Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors. J Cell Biol 170: 191–200.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mosesson Y, Mills GB, Yarden Y . (2008). Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer 8: 835–850.

    CAS  PubMed  Google Scholar 

  • Muraoka-Cook RS, Feng SM, Strunk KE, Earp 3rd HS . (2008). ErbB4/HER4: role in mammary gland development, differentiation and growth inhibition. J Mammary Gland Biol Neoplasia 13: 235–246.

    PubMed  PubMed Central  Google Scholar 

  • Myers JM, Martins GG, Ostrowski J, Stachowiak MK . (2003). Nuclear trafficking of FGFR1: a role for the transmembrane domain. J Cell Biochem 88: 1273–1291.

    CAS  PubMed  Google Scholar 

  • Naresh A, Thor AD, Edgerton SM, Torkko KC, Kumar R, Jones FE . (2008). The HER4/4ICD estrogen receptor coactivator and BH3-only protein is an effector of tamoxifen-induced apoptosis. Cancer Res 68: 6387–6395.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ni CY, Murphy MP, Golde TE, Carpenter G . (2001). Gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294: 2179–2181.

    CAS  PubMed  Google Scholar 

  • Offterdinger M, Schofer C, Weipoltshammer K, Grunt TW . (2002). c-erbB-3: a nuclear protein in mammary epithelial cells. J Cell Biol 157: 929–939.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Orth JD, Krueger EW, Weller SG, McNiven MA . (2006). A novel endocytic mechanism of epidermal growth factor receptor sequestration and internalization. Cancer Res 66: 3603–3610.

    CAS  PubMed  Google Scholar 

  • Peng H, Myers J, Fang X, Stachowiak EK, Maher PA, Martins GG et al. (2002). Integrative nuclear FGFR1 signaling (INFS) pathway mediates activation of the tyrosine hydroxylase gene by angiotensin II, depolarization and protein kinase C. J Neurochem 81: 506–524.

    CAS  PubMed  Google Scholar 

  • Pilecka I, Banach-Orlowska M, Miaczynska M . (2007). Nuclear functions of endocytic proteins. Eur J Cell Biol 86: 533–547.

    CAS  PubMed  Google Scholar 

  • Psyrri A, Yu Z, Weinberger PM, Sasaki C, Haffty B, Camp R et al. (2005). Quantitative determination of nuclear and cytoplasmic epidermal growth factor receptor expression in oropharyngeal squamous cell cancer by using automated quantitative analysis. Clin Cancer Res 11: 5856–5862.

    CAS  PubMed  Google Scholar 

  • Raper SE, Burwen SJ, Barker ME, Jones AL . (1987). Translocation of epidermal growth factor to the hepatocyte nucleus during rat liver regeneration. Gastroenterology 92: 1243–1250.

    CAS  PubMed  Google Scholar 

  • Reilly JF, Maher PA . (2001). Importin beta-mediated nuclear import of fibroblast growth factor receptor: role in cell proliferation. J Cell Biol 152: 1307–1312.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rink J, Ghigo E, Kalaidzidis Y, Zerial M . (2005). Rab conversion as a mechanism of progression from early to late endosomes. Cell 122: 735–749.

    CAS  PubMed  Google Scholar 

  • Saftig P, Klumperman J . (2009). Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10: 623–635.

    CAS  PubMed  Google Scholar 

  • Saksena S, Summers MD, Burks JK, Johnson AE, Braunagel SC . (2006). Importin-alpha-16 is a translocon-associated protein involved in sorting membrane proteins to the nuclear envelope. Nat Struct Mol Biol 13: 500–508.

    CAS  PubMed  Google Scholar 

  • Sandvig K, van Deurs B . (2002). Membrane traffic exploited by protein toxins. Annu Rev Cell Dev Biol 18: 1–24.

    CAS  PubMed  Google Scholar 

  • Sardi SP, Murtie J, Koirala S, Patten BA, Corfas G . (2006). Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell 127: 185–197.

    CAS  PubMed  Google Scholar 

  • Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J et al. (2007). Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 99: 628–638.

    CAS  PubMed  Google Scholar 

  • Sehat B, Tofigh A, Lin Y, Trocme E, Liljedahl U, Lagergren J et al. (2010). SUMOylation mediates the nuclear translocation and signaling of the IGF-1 receptor. Sci Signal 3: ra10.

    PubMed  Google Scholar 

  • Sequist LV, Lynch TJ . (2008). EGFR tyrosine kinase inhibitors in lung cancer: an evolving story. Annu Rev Med 59: 429–442.

    CAS  PubMed  Google Scholar 

  • Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P et al. (2005). Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci USA 102: 2760–2765.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sorkin A . (2004). Cargo recognition during clathrin-mediated endocytosis: a team effort. Curr Opin Cell Biol 16: 392–399.

    CAS  PubMed  Google Scholar 

  • Sorkin A, Goh LK . (2009). Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res 315: 683–696.

    CAS  PubMed  Google Scholar 

  • Sorkin A, von Zastrow M . (2009). Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol 10: 609–622.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Spooner RA, Smith DC, Easton AJ, Roberts LM, Lord JM . (2006). Retrograde transport pathways utilised by viruses and protein toxins. Virol J 3: 26.

    PubMed  PubMed Central  Google Scholar 

  • Stachowiak MK, Maher PA, Joy A, Mordechai E, Stachowiak EK . (1996). Nuclear localization of functional FGF receptor 1 in human astrocytes suggests a novel mechanism for growth factor action. Brain Res Mol Brain Res 38: 161–165.

    CAS  PubMed  Google Scholar 

  • Stachowiak MK, Maher PA, Stachowiak EK . (2007). Integrative nuclear signaling in cell development—a role for FGF receptor-1. DNA Cell Biol 26: 811–826.

    CAS  PubMed  Google Scholar 

  • Stewart CL, Roux KJ, Burke B . (2007). Blurring the boundary: the nuclear envelope extends its reach. Science 318: 1408–1412.

    CAS  PubMed  Google Scholar 

  • Stewart M . (2007). Molecular mechanism of the nuclear protein import cycle. Nat Rev Mol Cell Biol 8: 195–208.

    CAS  PubMed  Google Scholar 

  • Terry LJ, Shows EB, Wente SR . (2007). Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport. Science 318: 1412–1416.

    CAS  PubMed  Google Scholar 

  • Thompson M, Lauderdale S, Webster MJ, Chong VZ, McClintock B, Saunders R et al. (2007). Widespread expression of ErbB2, ErbB3 and ErbB4 in non-human primate brain. Brain Res 1139: 95–109.

    CAS  PubMed  Google Scholar 

  • Wang SC, Lien HC, Xia W, Chen IF, Lo HW, Wang Z et al. (2004). Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell 6: 251–261.

    CAS  PubMed  Google Scholar 

  • Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC et al. (2006). Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol 8: 1359–1368.

    CAS  PubMed  Google Scholar 

  • Wang SC, Hung MC . (2009). Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors. Clin Cancer Res 15: 6484–6489.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang ZH, Tian XX, Cheng Y, Yam GH, Ng HK, Ding MX et al. (1998). Association of EGFR gene fragments with nuclear matrices in glioblastoma cell lines. Anticancer Res 18: 4329–4332.

    CAS  PubMed  Google Scholar 

  • Wanner G, Mayer C, Kehlbach R, Rodemann HP, Dittmann K . (2008). Activation of protein kinase Cepsilon stimulates DNA-repair via epidermal growth factor receptor nuclear accumulation. Radiother Oncol 86: 383–390.

    CAS  PubMed  Google Scholar 

  • Weis K . (2003). Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell 112: 441–451.

    CAS  PubMed  Google Scholar 

  • Wells A, Marti U . (2002). Signalling shortcuts: cell-surface receptors in the nucleus? Nat Rev Mol Cell Biol 3: 697–702.

    CAS  PubMed  Google Scholar 

  • Williams CC, Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L et al. (2004). The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone. J Cell Biol 167: 469–478.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Williams RL, Urbe S . (2007). The emerging shape of the ESCRT machinery. Nat Rev Mol Cell Biol 8: 355–368.

    CAS  PubMed  Google Scholar 

  • Woodman P . (2009). ESCRT proteins, endosome organization and mitogenic receptor down-regulation. Biochem Soc Trans 37: 146–150.

    CAS  PubMed  Google Scholar 

  • Xia W, Wei Y, Du Y, Liu J, Chang B, Yu YL et al. (2009). Nuclear expression of epidermal growth factor receptor is a novel prognostic value in patients with ovarian cancer. Mol Carcinog 48: 610–617.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xie Y, Hung MC . (1994). Nuclear localization of p185neu tyrosine kinase and its association with transcriptional transactivation. Biochem Biophys Res Commun 203: 1589–1598.

    CAS  PubMed  Google Scholar 

  • Xu Y, Shao Y, Zhou J, Voorhees JJ, Fisher GJ . (2009). Ultraviolet irradiation-induces epidermal growth factor receptor (EGFR) nuclear translocation in human keratinocytes. J Cell Biochem 107: 873–880.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yarden Y . (2001). The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer 37 (Suppl 4): S3–S8.

    CAS  PubMed  Google Scholar 

  • Yarden Y, Sliwkowski MX . (2001). Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2: 127–137.

    CAS  PubMed  Google Scholar 

  • Zuleger N, Korfali N, Schirmer EC . (2008). Inner nuclear membrane protein transport is mediated by multiple mechanisms. Biochem Soc Trans 36: 1373–1377.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Institutes of Health Grants RO1 109311; the National Breast Cancer Foundation Inc.; the Sister Institutional fund from China Medical University Hospital and MD Anderson Cancer Center; Cancer Center Research of Excellence DOH TD-C-111-005 (Taiwan) (to M-CH), and National Science Council Taiwan Merit Postdoctoral Scholarship TMS-94-2B-001 (to Y-NW). In memoriam, Mrs Serena Lin-Guo for her courageous battle in breast cancer.

Author information

Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y-N Wang, H Yamaguchi, J-M Hsu & M-C Hung

  2. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    J-M Hsu & M-C Hung

  3. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan

    M-C Hung

  4. Asia University, Taichung, Taiwan

    M-C Hung

Authors
  1. Y-N Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J-M Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M-C Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M-C Hung.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, YN., Yamaguchi, H., Hsu, JM. et al. Nuclear trafficking of the epidermal growth factor receptor family membrane proteins. Oncogene 29, 3997–4006 (2010). https://doi.org/10.1038/onc.2010.157

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.157

Keywords

This article is cited by

Search

Advanced search

Quick links