[en] The ErbB receptors are tyrosine kinases that bind a wide variety of ligands. They are implicated in cell proliferation, generation of anti-apoptotic signals, differentiation, and cell migration. The over-expression of different Erb B receptors and/or the expression of aberrant mutant forms are responsible for the development of many human cancers. A simplified view of the mechanism of action of these receptors is that they are triggered when located at the cell surface and/or when present in endosomes.
In this review we will discuss a newly emergent, and more complex, picture in which ErbB receptors and their ligands translocate to the cell nucleus where they assume additional functions. The possible involvement of calmodulin in the translocation process will be discussed, as well. The development of new therapeutic strategies targeting the nuclear translocation system and/or the nuclear functions of ErbB receptors could help to control the rapid growth of certain types of tumor cells.
Weiss A, Schlessinger J. Switching signals on or off by receptor dimerization. Cell 1998;94:277-80.
Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annu Rev Biochem 2000;69:373-98.
Carraway KL III, Sweeney C. Localization and modulation of erbB receptor tyrosine kinases. Curr Op Cell Biol 2001;13:125-30.
Alroy I, Yarden Y. The ErbB signaling netwok in embriogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett 1997;410:83-6.
Citri A, Skaria KB, Yarden Y. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res 2003;284: 54-65.
Kim H, Muller WJ. The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis. Exp Cell Res 1999;253:78-87.
Olayioye MA, Neve RM, Lane HA, et al. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000;19:3159-67.
Fantl WJ, Johnson DE, Williams LT. Signalling by receptor tyrosine kinases. Annu Rev Biochem 1993;62:453-81.
Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000;103:211-25.
Waterman H, Yarden Y. Molecular mechanisms underlying endocytosis and sorting of ErbB receptor tyrosine kinases. FEBS Lett 2001;490:142-52.
Wang Y, Pennock S, Chen X, et al. Endosomal signaling of epidermal growth factor receptor stimulates signal transduction pathway leading to cell survival. Mol Cell Biol 2002;22:7279-90.
Jans DA. Nuclear signaling pathways for polypeptide ligands and their membrane receptors? FASEB J 1994; 8:841-7.
Pederson T. Growth factors in the nucleolus? J Cell Biol 1998;143:279-81.
Wells A, Marti U. Signalling shortcuts: cell-surface receptors in the nucleus? Nat Rev Mol Cell Biol 2002; 3:697-702.
Johnson LK, Vlodavsky I, Baxter JD, et al. Nuclear accumulation of epidermal growth factor in cultured rat pituitary cells. Nature 1980;287:340-3.
Rakowicz-Szulczynska EM, Rodeck U, Herlyn M, et al. Chromatin binding of epidermal growth factor, nerve growth factor, and platelet-derived growth factor in cells bearing the appropriate surface receptors. Proc Natl Acad Sci USA 1986;83:3728-32.
Raper SE, Burwen SJ, Barker ME, et al. Translocation of epidermal growth factor to the hepatocyte nucleus during rat liver regeneration. Gastroenterology 1987;92:1243-50.
Rakowicz-Szulczynska EM, Otwiaska D, Rodeck U, et al. Epidermal growth factor (EGF) and monoclonal antibody to cell surface EGF receptor bind to the same chromatin receptor. Arch Biochem Biophys 1989; 268:456-64.
Jiang LW, Schindler M. Nucleocytoplasmic transport is enhanced concomitant with nuclear accumulation of epidermal growth factor (EGF) binding activity in both 3T3-1 and EGF receptor reconstituted NR-6 fibroblasts. J Cell Biol 1990;10:559-68.
Marti U, Burwen SJ, Wells A, et al. Localization of epidermal growth factor receptor in hepatocyte nuclei. Hepatology 1991;13:15-20.
Marti U, Ruchti C, Kampf J, et al. Nuclear localization of epidermal growth factor and epidermal growth factor receptors in human thyroid tissues. Thyroid 2001; 11:137-45.
Modrell B, McDonald VL, Shoyab M. The interaction of amphiregulin with nuclei and putative nuclear localization sequence binding proteins. Growth Factors 1992; 7:305-14.
Kimura H. Schwannoma-derived growth factor must be transported into the nucleus to exert its mitogenic activity. Proc Natl Acad Sci USA 1993;90:2165-9.
Li W, Park JW, Nuijens A, et al. Herregulin is rapidly translocated to the nucleus and its transport is correlated with c-myc induction in breast cancer cells. Oncogene 1996;12:2473-7.
Offterdinger M, Schofer C, Weipoltshammer K, et al. cerbB-3: a nuclear protein in mammary epithelial cells. J Cell Biol 2002;157:929-39.
Johnson GR, Saeki T, Auersperg N, et al. Response to and expression of amphiregulin by ovarian carcinoma and normal ovarian surface epithelial cells: nuclear localization of endogenous amphiregulin. Biochem Biophys Res Commun 1991;180:481-8.
Waugh MG, Hsuan JJ. EGF receptors as transcription factors: ridiculous or sublime? Nat Cell Biol 2001;3: E209-11.
Heldin C-H, Ericsson J. RIPping tyrosine kinase receptors apart. Science 2001;294:2111-3.
Raben DM, Baldassare JJ. More than scratching the surface: mitogen receptors as transcription factors? Trends Endocrinol Metabol 2002;13:93-4.
Mroczkowski B, Mosig G, Cohen S. ATP-stimulated interaction between epidermal growth factor receptor and supercoiled DNA. Nature 1984;309:270-3.
Basu M, Frick K, Sen-Majumdar A, et al. EGF receptorassociated DNA-nicking activity is due to a Mr-100,000 dissociable protein. Nature 1985;316:640-1.
Carpentier JL, Rees AR, Gregoriou M, et al. Subcellular distribution of the external and internal domains of the EGF receptor in A-431 cells. Exp Cell Res 1986;166:312-26.
Marti U, Hug M. Acinar and cellular distribution and mRNA expression of the epidermal growth factor receptor are changed during liver regeneration. J Hepatol 1995;23:318-27.
Zimmermann H, Ganz P, Zimmermann A, et al. The overexpression of proliferating cell nuclear antigen in biliary cirrhosis in the rat and its relationship with epidermal growth factor receptor. J Hepatol 1995;23:459-64.
Lin S-Y, Makino K, Xia WY, et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol 2001;3:802-8.
Kamio T, Shigematsu K, Sou H, et al. Immunohistochemical expression of epidermal growth factor receptors in human adrenocortical carcinoma. Hum Pathol 1990;21:277-82.
Lipponen P, Eskelinen M. Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and long-term prognosis. Br J Cancer 1994;69:1120-5.
Tervahauta A, Syrjanen S, Syrjanen K. Epidermal growth factor receptor, c-erbB-2 proto-oncogene and estrogen receptor expression in human papillomavirus lesions of the uterin cervix. Int J Gynecol Pathol 1994; 13:234-40.
Holt SJ, Alexander P, Inman CB, et al. Epidermal growth factor induced tyrosine phosphorylation of nuclear proteins associated with translocation of epidermal growth factor receptor into the nucleus. Biochem Pharmacol 1994;47:117-26.
Holt SJ, Alexander P, Inman CB, et al. Ligand-induced translocation of epidermal growth factor receptor to the nucleus of NR6/HER fibroblasts is serum dependent. Exp Cell Res 1995;217:554-8.
Oksvold M, Huitfeldt H, Stang E, et al. Localizing the EGF receptor. Nat Cell Biol 2002;4:E22.
Bourguignon L, Lan K-H, Singleton P, et al. Localizing the EGF receptor-Reply. Nat Cell Biol 2002;4:E22-3.
Xie Y, Hung MC. Nuclear localization of p185neu tyrosine kinase and its association with transcriptional transactivation. Biochem Biophys Res Commun 1994;203:1589-98.
Srinivasan R, Poulsom R, Hurst HC, et al. Expression of the c-erbB-4/HER4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types. J Pathol 1998;185:236-45.
Srinivasan R, Gillett CE, Barnes DM, et al. Nuclear expression of the c-erbB-4/HER-4 growth factor receptor in invasive breast cancers. Cancer Res 2000; 60:1483-7.
Ni C-Y, Murphy MP, Golde TE, et al. Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001;294:2179-81.
Lee H-J, Jung K-M, Huang YZ, et al. Presenilin-dependent ?-secretase-like intramembrane cleavage of ErbB4. J Biol Chem 2002;277:6318-23.
Takasugi N, Tomita T, Hayashi I, et al. The role of presenilin cofactors in the g-secretase complex. Nature 2003; 422:438-41.
Bargmann CI, Hyung MC, Weinberg RA. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell 1986;45:649-57.
Marti U, Wells A. The nuclear accumulation of variant epidermal growth factor receptor (EGFR) lacking the transmembrane domain requires coexpression of a fulllength EGFR. Mol Cell Biol Res Commun 2000;3:8-14.
Sweitzer TD, Hanover JA. Calmodulin activates nuclear protein import: a link between signal transduction and nuclear transport. Proc Natl Acad Sci USA 1996; 93:14574-9.
San José E, Benguría A, Geller P, Villalobo A. Calmodulin inhibits the epidermal growth factor receptor tyrosine kinase. J Biol Chem 1992;267:15237-45.
Martín-Nieto J, Villalobo A. The human epidermal growth factor receptor contains a juxtamembrane calmodulin-binding site. Biochemistry 1998;37:227-36.
Aifa S, Johansen K, Nilsson UK, et al. Interactions between the juxtamembrane domain of the EGFR and calmodulin measured by surface plasmon resonance. Cell Signal 2002;14:1005-13.
Li H, Villalobo A. Evidence for the direct interaction between calmodulin and the human epidermal growth factor receptor. Biochem J 2002;362:499-505.
Tebar F, Villalonga P, Sorkina T, et al. Calmodulin regulates intracellular trafficking of epidermal growth factor receptor and the MAPK signaling pathway. Mol Biol Cell 2002;13:2057-68.
Martín-Nieto J, Cusidó-Hita DM, Li H, et al. Regulation of ErbB receptors by calmodulin. Rec Res Develop Biochem 2002;3:41-58.
Antonsson A, Hughes K, Edin S, et al. Regulation of c-Rel nuclear localization by binding of Ca2+/calmodulin. Mol Cell Biol 2003;23:1418-27.
Benguría A, Hernández-Perera O, Martínez-Pastor MT, et al. Phosphorylation of calmodulin by the epidermalgrowth-factor-receptor tyrosine kinase. Eur J Biochem 1994;224:909-16.
Villalobo A, Ruano MJ, Palomo-Jiménez PI, et al. The epidermal growth factor receptor and the calcium signal. In: Pochet R, et al. editors. Calcium: the molecular basis of calcium action in biology and medicine. Boston MA: Kluwer Academic Publishers, 2000;pp.287-303.
Benaim G, Villalobo A. Phosphorylation of calmodulin: functional implications. Eur J Biochem 2002;269:3619-31.
Bollen M, Beullens M. Signaling by protein phosphatases in the nucleus. Trends Cell Biol 2002;12:138-45.
Tiganis T, Bennett AM, Ravichandran KS, et al. Epidermal growth factor receptor and the adaptor protein p52Shc are specific substrates of T-cell protein tyrosine phosphatase. Mol Cell Biol 1998;18:1622-34.
Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000;19:6550-65.
Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs 2000;59:753-67.
Yarden Y. The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer 2001;37:S3-8.
Zwick E, Bange J, Ullrich A. Receptor tyrosine kinases as targets for anticancer drugs. Trends Mol Med 2002; 8:17-23.
Reilly RM, Kiarash R, Cameron RG, et al. 111In-labeled EGF is selectively radiotoxic to human breast cancer cells overexpressing EGFR. J Nucl Med 2000;41:429-38.
Carpenter G. Nuclear localization and possible functions of receptor tyrosine kinases. Curr Op Cell Biol 2003; 15:143-8.
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