DOI QR코드

DOI QR Code

Endocytic Regulation of EGFR Signaling

  • Chung, Byung-Min (Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Johns Hopkins University)
  • Received : 2012.04.09
  • Accepted : 2012.04.18
  • Published : 2012.06.30

Abstract

Epidermal growth factor receptor (EGFR) is a member of the ErbB family (ErbB1-4) of receptor tyrosine kinases (RTKs). EGFR controls numerous physiological functions, including cell proliferation, migration, differentiation and survival. Importantly, aberrant signaling by EGFR has been linked to human cancers in which EGFR and its various ligands are frequently overexpressed or mutated. EGFR coordinates activation of multiple downstream factors and is subject of various regulatory processes as it mediates biology of the cell it resides in. Therefore, many studies have been devoted to understanding EGFR biology and targeting the protein for the goal of controlling tumor in clinical settings. Endocytic regulation of EGFR offers a promising area for targeting EGFR activity. Upon ligand binding, the activated receptor undergoes endocytosis and becomes degraded in lysosome, thereby terminating the signal. En route to lysosome, the receptor becomes engaged in activating various signaling pathways including PI-3K, MAPK and Src, and endocytosis may offer both spatial and temporal regulation of downstream target activation. Therefore, endocytosis is an important regulator of EGFR signaling, and increasing emphasis is being placed on endocytosis in terms of cancer treatment and understanding of the disease. In this review, EGFR signaling pathway and its intricate regulation by endocytosis will be discussed.

References

  1. Gschwind, A., Fischer, O.M., and Ullrich, A. (2004). The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 4, 361-370. https://doi.org/10.1038/nrc1360
  2. Wiley, H.S. (2003). Trafficking of the ErbB receptors and its influence on signaling. Exp Cell Res 284, 78-88. https://doi.org/10.1016/S0014-4827(03)00002-8
  3. Miettinen, P.J., Berger, J.E., Meneses, J., Phung, Y., Pedersen, R.A., Werb, Z., and Derynck, R. (1995). Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337- 341. https://doi.org/10.1038/376337a0
  4. Threadgill, D.W., Dlugosz, A.A., Hansen, L.A., Tennenbaum, T., Lichti, U., Yee, D., LaMantia, C., Mourton, T., Herrup, K., Harris, R.C., et al. (1995). Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269, 230-234. https://doi.org/10.1126/science.7618084
  5. Yarden, Y., and Sliwkowski, M.X. (2001). Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2, 127-137. https://doi.org/10.1038/35052073
  6. Herbst, R.S. (2004). Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 59, 21-26. https://doi.org/10.1016/j.ijrobp.2003.10.027
  7. Di Marco, E., Pierce, J.H., Fleming, T.P., Kraus, M.H., Molloy, C.J., Aaronson, S.A., and Di Fiore, P.P. (1989). Autocrine interaction between TGF alpha and the EGF-receptor: quantitative requirements for induction of the malignant phenotype. Oncogene 4, 831-838.
  8. Sturla, L.M., Amorino, G., Alexander, M.S., Mikkelsen, R.B., Valerie, K., and Schmidt-Ullrichr, R.K. (2005). Requirement of Tyr-992 and Tyr-1173 in phosphorylation of the epidermal growth factor receptor by ionizing radiation and modulation by SHP2. J Biol Chem 280, 14597-14604. https://doi.org/10.1074/jbc.M413287200
  9. Nicholson, R.I., Gee, J.M., and Harper, M.E. (2001). EGFR and cancer prognosis. Eur J Cancer 37 Suppl 4, S9-15.
  10. Hynes, N.E., and MacDonald, G. (2009). ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21, 177-184. https://doi.org/10.1016/j.ceb.2008.12.010
  11. Sattler, M., Abidoye, O., and Salgia, R. (2008). EGFR-targeted therapeutics: focus on SCCHN and NSCLC. Scientific World Journal 8, 909-919. https://doi.org/10.1100/tsw.2008.117
  12. Schulze, W.X., Deng, L., and Mann, M. (2005). Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol Syst Biol 1, 2005 0008.
  13. Schlessinger, J. (2000). Cell signaling by receptor tyrosine kinases. Cell 103, 211-225. https://doi.org/10.1016/S0092-8674(00)00114-8
  14. Mattoon, D.R., Lamothe, B., Lax, I., and Schlessinger, J. (2004). The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathway. BMC Biol 2, 24. https://doi.org/10.1186/1741-7007-2-24
  15. Haugh, J.M., Huang, A.C., Wiley, H.S., Wells, A., and Lauffenburger, D.A. (1999). Internalized epidermal growth factor receptors participate in the activation of p21(ras) in fibroblasts. J Biol Chem 274, 34350-34360. https://doi.org/10.1074/jbc.274.48.34350
  16. Marmor, M.D., and Yarden, Y. (2004). Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene 23, 2057- 2070. https://doi.org/10.1038/sj.onc.1207390
  17. Conner, S.D., and Schmid, S.L. (2003). Regulated portals of entry into the cell. Nature 422, 37-44. https://doi.org/10.1038/nature01451
  18. Katzmann, D.J., Odorizzi, G., and Emr, S.D. (2002). Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol 3, 893- 905. https://doi.org/10.1038/nrm973
  19. Maxfield, F.R., and McGraw, T.E. (2004). Endocytic recycling. Nat Rev Mol Cell Biol 5, 121-132. https://doi.org/10.1038/nrm1315
  20. Worby, C.A., and Dixon, J.E. (2002). Sorting out the cellular functions of sorting nexins. Nat Rev Mol Cell Biol 3, 919-931. https://doi.org/10.1038/nrm974
  21. de Melker, A.A., van der Horst, G., Calafat, J., Jansen, H., and Borst, J. (2001). c-Cbl ubiquitinates the EGF receptor at the plasma membrane and remains receptor associated throughout the endocytic route. J Cell Sci 114, 2167-2178.
  22. Duan, L., Miura, Y., Dimri, M., Majumder, B., Dodge, I.L., Reddi, A.L., Ghosh, A., Fernandes, N., Zhou, P., Mullane-Robinson, K., et al. (2003). Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis. J Biol Chem 278, 28950-28960. https://doi.org/10.1074/jbc.M304474200
  23. Haglund, K., Sigismund, S., Polo, S., Szymkiewicz, I., Di Fiore, P.P., and Dikic, I. (2003). Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol 5, 461-466. https://doi.org/10.1038/ncb983
  24. Huang, F., Khvorova, A., Marshall, W., and Sorkin, A. (2004). Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference. J Biol Chem 279, 16657-16661. https://doi.org/10.1074/jbc.C400046200
  25. Kowanetz, K., Crosetto, N., Haglund, K., Schmidt, M.H., Heldin, C.H., and Dikic, I. (2004). Suppressors of T-cell receptor signaling Sts-1 and Sts-2 bind to Cbl and inhibit endocytosis of receptor tyrosine kinases. J Biol Chem 279, 32786-32795. https://doi.org/10.1074/jbc.M403759200
  26. Lynch, D.K., Winata, S.C., Lyons, R.J., Hughes, W.E., Lehrbach, G.M., Wasinger, V., Corthals, G., Cordwell, S., and Daly, R.J. (2003). A Cortactin- CD2-associated protein (CD2AP) complex provides a novel link between epidermal growth factor receptor endocytosis and the actin cytoskeleton. J Biol Chem 278, 21805-21813. https://doi.org/10.1074/jbc.M211407200
  27. Stang, E., Blystad, F.D., Kazazic, M., Bertelsen, V., Brodahl, T., Raiborg, C., Stenmark, H., and Madshus, I.H. (2004). Cbl-dependent ubiquitination is required for progression of EGF receptors into clathrin-coated pits. Mol Biol Cell 15, 3591-3604. https://doi.org/10.1091/mbc.E04-01-0041
  28. Feng, Q., Baird, D., Peng, X., Wang, J., Ly, T., Guan, J.L., and Cerione, R.A. (2006). Cool-1 functions as an essential regulatory node for EGF receptor- and Src-mediated cell growth. Nat Cell Biol 8, 945-956. https://doi.org/10.1038/ncb1453
  29. Katz, M., Amit, I., Citri, A., Shay, T., Carvalho, S., Lavi, S., Milanezi, F., Lyass, L., Amariglio, N., Jacob-Hirsch, J., et al. (2007). A reciprocal tensin- 3-cten switch mediates EGF-driven mammary cell migration. Nat Cell Biol 9, 961-969. https://doi.org/10.1038/ncb1622
  30. Lu, Q., Hope, L.W., Brasch, M., Reinhard, C., and Cohen, S.N. (2003). TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation. Proc Natl Acad Sci U S A 100, 7626-7631. https://doi.org/10.1073/pnas.0932599100
  31. Mizuno, E., Kawahata, K., Kato, M., Kitamura, N., and Komada, M. (2003). STAM proteins bind ubiquitinated proteins on the early endosome via the VHS domain and ubiquitin-interacting motif. Mol Biol Cell 14, 3675- 3689. https://doi.org/10.1091/mbc.E02-12-0823
  32. Sigismund, S., Woelk, T., Puri, C., Maspero, E., Tacchetti, C., Transidico, P., Di Fiore, P.P., and Polo, S. (2005). Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci U S A 102, 2760-2765. https://doi.org/10.1073/pnas.0409817102
  33. Chen, H., and De Camilli, P. (2005). The association of epsin with ubiquitinated cargo along the endocytic pathway is negatively regulated by its interaction with clathrin. Proc Natl Acad Sci U S A 102, 2766-2771. https://doi.org/10.1073/pnas.0409719102
  34. Sigismund, S., Argenzio, E., Tosoni, D., Cavallaro, E., Polo, S., and Di Fiore, P.P. (2008). Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation. Dev Cell 15, 209-219. https://doi.org/10.1016/j.devcel.2008.06.012
  35. Soubeyran, P., Kowanetz, K., Szymkiewicz, I., Langdon, W.Y., and Dikic, I. (2002). Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature 416, 183-187. https://doi.org/10.1038/416183a
  36. Huang, F., and Sorkin, A. (2005). Growth factor receptor binding protein 2-mediated recruitment of the RING domain of Cbl to the epidermal growth factor receptor is essential and sufficient to support receptor endocytosis. Mol Biol Cell 16, 1268-1281. https://doi.org/10.1091/mbc.E04-09-0832
  37. Pennock, S., and Wang, Z. (2008). A tale of two Cbls: interplay of c-Cbl and Cbl-b in epidermal growth factor receptor downregulation. Mol Cell Biol 28, 3020-3037. https://doi.org/10.1128/MCB.01809-07
  38. Sadowski, L., Pilecka, I., and Miaczynska, M. (2009). Signaling from endosomes: location makes a difference. Exp Cell Res 315, 1601-1609. https://doi.org/10.1016/j.yexcr.2008.09.021
  39. Haugh, J.M., Schooler, K., Wells, A., Wiley, H.S., and Lauffenburger, D.A. (1999). Effect of epidermal growth factor receptor internalization on regulation of the phospholipase C-gamma1 signaling pathway. J Biol Chem 274, 8958-8965. https://doi.org/10.1074/jbc.274.13.8958
  40. Vieira, A.V., Lamaze, C., and Schmid, S.L. (1996). Control of EGF receptor signaling by clathrin-mediated endocytosis. Science 274, 2086-2089. https://doi.org/10.1126/science.274.5295.2086
  41. Tran, D.D., Russell, H.R., Sutor, S.L., van Deursen, J., and Bram, R.J. (2003). CAML is required for efficient EGF receptor recycling. Dev Cell 5, 245- 256. https://doi.org/10.1016/S1534-5807(03)00207-7
  42. Chung, B.M., Dimri, M., George, M., Reddi, A.L., Chen, G., Band, V., and Band, H. (2009). The role of cooperativity with Src in oncogenic transformation mediated by non-small cell lung cancer-associated EGF receptor mutants. Oncogene 28, 1821-1832. https://doi.org/10.1038/onc.2009.31
  43. Sordella, R., Bell, D.W., Haber, D.A., and Settleman, J. (2004). Gefitinibsensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305, 1163-1167. https://doi.org/10.1126/science.1101637
  44. Chung, B.M., Raja, S.M., Clubb, R.J., Tu, C., George, M., Band, V., and Band, H. (2009). Aberrant trafficking of NSCLC-associated EGFR mutants through the endocytic recycling pathway promotes interaction with Src. BMC Cell Biol 10, 84. https://doi.org/10.1186/1471-2121-10-84
  45. Jekely, G., Sung, H.H., Luque, C.M., and Rorth, P. (2005). Regulators of endocytosis maintain localized receptor tyrosine kinase signaling in guided migration. Dev Cell 9, 197-207. https://doi.org/10.1016/j.devcel.2005.06.004
  46. Reynolds, A.B., and Roczniak-Ferguson, A. (2004). Emerging roles for p120-catenin in cell adhesion and cancer. Oncogene 23, 7947-7956. https://doi.org/10.1038/sj.onc.1208161
  47. Clague, M.J., and Urbe, S. (2001). The interface of receptor trafficking and signalling. J Cell Sci 114, 3075-3081.
  48. Wherlock, M., Gampel, A., Futter, C., and Mellor, H. (2004). Farnesyltransferase inhibitors disrupt EGF receptor traffic through modulation of the RhoB GTPase. J Cell Sci 117, 3221-3231. https://doi.org/10.1242/jcs.01193
  49. Kassenbrock, C.K., Hunter, S., Garl, P., Johnson, G.L., and Anderson, S.M. (2002). Inhibition of Src family kinases blocks epidermal growth factor (EGF)-induced activation of Akt, phosphorylation of c-Cbl, and ubiquitination of the EGF receptor. J Biol Chem 277, 24967-24975. https://doi.org/10.1074/jbc.M201026200
  50. Wilde, A., Beattie, E.C., Lem, L., Riethof, D.A., Liu, S.H., Mobley, W.C., Soriano, P., and Brodsky, F.M. (1999). EGF receptor signaling stimulates SRC kinase phosphorylation of clathrin, influencing clathrin redistribution and EGF uptake. Cell 96, 677-687. https://doi.org/10.1016/S0092-8674(00)80578-4
  51. Ahn, S., Kim, J., Lucaveche, C.L., Reedy, M.C., Luttrell, L.M., Lefkowitz, R.J., and Daaka, Y. (2002). Src-dependent tyrosine phosphorylation regulates dynamin self-assembly and ligand-induced endocytosis of the epidermal growth factor receptor. J Biol Chem 277, 26642-26651. https://doi.org/10.1074/jbc.M201499200
  52. Yokouchi, M., Kondo, T., Sanjay, A., Houghton, A., Yoshimura, A., Komiya, S., Zhang, H., and Baron, R. (2001). Src-catalyzed phosphorylation of c-Cbl leads to the interdependent ubiquitination of both proteins. J Biol Chem 276, 35185-35193. https://doi.org/10.1074/jbc.M102219200