Get Epidermal Growth Factor Receptor essential facts below. View Videos or join the Epidermal Growth Factor Receptor discussion. Add Epidermal Growth Factor Receptor to your PopFlock.com topic list for future reference or share this resource on social media.
Deficient signaling of the EGFR and other receptor tyrosine kinases in humans is associated with diseases such as Alzheimer's, while over-expression is associated with the development of a wide variety of tumors. Interruption of EGFR signalling, either by blocking EGFR binding sites on the extracellular domain of the receptor or by inhibiting intracellular tyrosine kinase activity, can prevent the growth of EGFR-expressing tumours and improve the patient's condition.
EGFR signaling cascades
Diagram of the EGF receptor highlighting important domains
Epidermal growth factor receptor (EGFR) is a transmembrane protein that is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor ? (TGF?) ErbB2 has no known direct activating ligand, and may be in an activated state constitutively or become active upon heterodimerization with other family members such as EGFR.
Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer. - although there is some evidence that preformed inactive dimers may also exist before ligand binding. In addition to forming homodimers after ligand binding, EGFR may pair with another member of the ErbB receptor family, such as ErbB2/Her2/neu, to create an activated heterodimer. There is also evidence to suggest that clusters of activated EGFRs form, although it remains unclear whether this clustering is important for activation itself or occurs subsequent to activation of individual dimers.
EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine (Y) residues in the C-terminal domain of EGFR occurs. These include Y992, Y1045, Y1068, Y1148 and Y1173, as shown in the adjacent diagram. This autophosphorylation elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation. Such proteins modulate phenotypes such as cell migration, adhesion, and proliferation. Activation of the receptor is important for the innate immune response in human skin. The kinase domain of EGFR can also cross-phosphorylate tyrosine residues of other receptors it is aggregated with, and can itself be activated in that manner.
Aberrant EGFR signaling has been implicated in psoriasis, eczema and atherosclerosis. However, its exact roles in these conditions are ill-defined.
A single child displaying multi-organ epithelial inflammation was found to have a homozygous loss of function mutation in the EGFR gene. The pathogenicity of the EGFR mutation was supported by in vitro experiments and functional analysis of a skin biopsy. His severe phenotype reflects many previous research findings into EGFR function. His clinical features included a papulopustular rash, dry skin, chronic diarrhoea, abnormalities of hair growth, breathing difficulties and electrolyte imbalances.
Another method is using small molecules to inhibit the EGFR tyrosine kinase, which is on the cytoplasmic side of the receptor. Without kinase activity, EGFR is unable to activate itself, which is a prerequisite for binding of downstream adaptor proteins. Ostensibly by halting the signaling cascade in cells that rely on this pathway for growth, tumor proliferation and migration is diminished. Gefitinib, erlotinib, brigatinib and lapatinib (mixed EGFR and ERBB2 inhibitor) are examples of small molecule kinase inhibitors.
CimaVax-EGF, an active vaccine targeting EGF as the major ligand of EGF, uses a different approach, raising antibodies against EGF itself, thereby denying EGFR-dependent cancers of a proliferative stimulus; it is in use as a cancer therapy against non-small-cell lung carcinoma (the most common form of lung cancer) in Cuba, and is undergoing further trials for possible licensing in Japan, Europe, and the United States.
There are several quantitative methods available that use protein phosphorylation detection to identify EGFR family inhibitors.
New drugs such as osimertinib, gefitinib, erlotinib and brigatinib directly target the EGFR. Patients have been divided into EGFR-positive and EGFR-negative, based upon whether a tissue test shows a mutation. EGFR-positive patients have shown a 60% response rate, which exceeds the response rate for conventional chemotherapy.
However, many patients develop resistance. Two primary sources of resistance are the T790M Mutation and MET oncogene. However, as of 2010 there was no consensus of an accepted approach to combat resistance nor FDA approval of a specific combination. Clinical trial phase II results reported for brigatinib targeting the T790M mutation, and brigatinib received Breakthrough Therapy designation status by FDA in Feb. 2015.
The most common adverse effect of EGFR inhibitors, found in more than 90% of patients, is a papulopustular rash that spreads across the face and torso; the rash's presence is correlated with the drug's antitumor effect. In 10% to 15% of patients the effects can be serious and require treatment.
Some tests are aiming at predicting benefit from EGFR treatment, as Veristrat.
Laboratory research using genetically engineered stem cells to target EGFR in mice was reported in 2014 to show promise. EGFR is a well-established target for monoclonal antibodies and specific tyrosine kinase inhibitors.
Target for imaging agents
Imaging agents have been developed which identify EGFR-dependent cancers using labeled EGF. The feasibility of in vivo imaging of EGFR expression has been demonstrated in several studies.
Epidermal growth factor receptor has been shown to interact with:
^Sebastian J, Richards RG, Walker MP, Wiesen JF, Werb Z, Derynck R, Hom YK, Cunha GR, DiAugustine RP (September 1998). "Activation and function of the epidermal growth factor receptor and erbB-2 during mammary gland morphogenesis". Cell Growth & Differentiation. 9 (9): 777-85. PMID9751121.
^McBryan J, Howlin J, Napoletano S, Martin F (June 2008). "Amphiregulin: role in mammary gland development and breast cancer". Journal of Mammary Gland Biology and Neoplasia. 13 (2): 159-69. doi:10.1007/s10911-008-9075-7. PMID18398673.
^Kenney NJ, Bowman A, Korach KS, Barrett JC, Salomon DS (May 2003). "Effect of exogenous epidermal-like growth factors on mammary gland development and differentiation in the estrogen receptor-alpha knockout (ERKO) mouse". Breast Cancer Research and Treatment. 79 (2): 161-73. doi:10.1023/a:1023938510508. PMID12825851.
^Kenney NJ, Smith GH, Rosenberg K, Cutler ML, Dickson RB (December 1996). "Induction of ductal morphogenesis and lobular hyperplasia by amphiregulin in the mouse mammary gland". Cell Growth & Differentiation. 7 (12): 1769-81. PMID8959346.
^Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (June 2004). "EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy". Science. 304 (5676): 1497-500. doi:10.1126/science.1099314. PMID15118125.
^Yan L, Beckman RA (October 2005). "Pharmacogenetics and pharmacogenomics in oncology therapeutic antibody development". BioTechniques. 39 (4): 565-8. doi:10.2144/000112043. PMID16235569.
^Rodríguez PC, Rodríguez G, González G, Lage A (Winter 2010). "Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy". MEDICC Review. 12 (1): 17-23. PMID20387330.
^Olive DM (October 2004). "Quantitative methods for the analysis of protein phosphorylation in drug development". Expert Review of Proteomics. 1 (3): 327-41. doi:10.1586/147894184.108.40.2067. PMID15966829.
^Lacouture ME (October 2006). "Mechanisms of cutaneous toxicities to EGFR inhibitors". Nature Reviews. Cancer. 6 (10): 803-12. doi:10.1038/nrc1970. PMID16990857.
^Molina-Pinelo S, Pastor MD, Paz-Ares L (February 2014). "VeriStrat: a prognostic and/or predictive biomarker for advanced lung cancer patients?". Expert Review of Respiratory Medicine. 8 (1): 1-4. doi:10.1586/17476348.2014.861744. PMID24308656.
^Lucas LJ, Tellez CA, Castilho ML, Lee CL, Hupman MA, Vieira LS, Ferreira I, Raniero L, Hewitt KC (May 2015). "Development of a sensitive, stable and EGFR-specific molecular imaging agent for surface enhanced Raman spectroscopy". Journal of Raman Spectroscopy. 46 (5): 434-446. doi:10.1002/jrs.4678.
^Lucas LJ, Chen XK, Smith AJ, Korbelik M, Zeng, Haitian L, Lee PW, Hewitt KC (23 January 2015). "Aggregation of nanoparticles in endosomes and lysosomes produces surface-enhanced Raman spectroscopy". Journal of Nanophotonics. 9 (1): 093094-1-14. doi:10.1117/1.JNP.9.093094.
^Bonaccorsi L, Carloni V, Muratori M, Formigli L, Zecchi S, Forti G, Baldi E (October 2004). "EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen-sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)". International Journal of Cancer. 112 (1): 78-86. doi:10.1002/ijc.20362. hdl:2158/395766. PMID15305378.
^Bonaccorsi L, Muratori M, Carloni V, Marchiani S, Formigli L, Forti G, Baldi E (August 2004). "The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells". Steroids. 69 (8-9): 549-52. doi:10.1016/j.steroids.2004.05.011. hdl:2158/395763. PMID15288768.
^Kim SW, Hayashi M, Lo JF, Yang Y, Yoo JS, Lee JD (January 2003). "ADP-ribosylation factor 4 small GTPase mediates epidermal growth factor receptor-dependent phospholipase D2 activation". The Journal of Biological Chemistry. 278 (4): 2661-8. doi:10.1074/jbc.M205819200. PMID12446727.
^ abCouet J, Sargiacomo M, Lisanti MP (November 1997). "Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities". The Journal of Biological Chemistry. 272 (48): 30429-38. doi:10.1074/jbc.272.48.30429. PMID9374534.
^ abEttenberg SA, Keane MM, Nau MM, Frankel M, Wang LM, Pierce JH, Lipkowitz S (March 1999). "cbl-b inhibits epidermal growth factor receptor signaling". Oncogene. 18 (10): 1855-66. doi:10.1038/sj.onc.1202499. PMID10086340.
^Keane MM, Ettenberg SA, Nau MM, Banerjee P, Cuello M, Penninger J, Lipkowitz S (June 1999). "cbl-3: a new mammalian cbl family protein". Oncogene. 18 (22): 3365-75. doi:10.1038/sj.onc.1202753. PMID10362357.
^Wang Z, Wang M, Lazo JS, Carr BI (May 2002). "Identification of epidermal growth factor receptor as a target of Cdc25A protein phosphatase". The Journal of Biological Chemistry. 277 (22): 19470-5. doi:10.1074/jbc.M201097200. PMID11912208.
^Hashimoto Y, Katayama H, Kiyokawa E, Ota S, Kurata T, Gotoh N, Otsuka N, Shibata M, Matsuda M (July 1998). "Phosphorylation of CrkII adaptor protein at tyrosine 221 by epidermal growth factor receptor". The Journal of Biological Chemistry. 273 (27): 17186-91. doi:10.1074/jbc.273.27.17186. PMID9642287.
^Hazan RB, Norton L (April 1998). "The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton". The Journal of Biological Chemistry. 273 (15): 9078-84. doi:10.1074/jbc.273.15.9078. PMID9535896.
^Schroeder JA, Adriance MC, McConnell EJ, Thompson MC, Pockaj B, Gendler SJ (June 2002). "ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas". The Journal of Biological Chemistry. 277 (25): 22692-8. doi:10.1074/jbc.M201975200. PMID11950845.
^Takahashi K, Suzuki K, Tsukatani Y (July 1997). "Induction of tyrosine phosphorylation and association of beta-catenin with EGF receptor upon tryptic digestion of quiescent cells at confluence". Oncogene. 15 (1): 71-8. doi:10.1038/sj.onc.1201160. PMID9233779.
^Santra M, Reed CC, Iozzo RV (September 2002). "Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope". The Journal of Biological Chemistry. 277 (38): 35671-81. doi:10.1074/jbc.M205317200. PMID12105206.
^Iozzo RV, Moscatello DK, McQuillan DJ, Eichstetter I (February 1999). "Decorin is a biological ligand for the epidermal growth factor receptor". The Journal of Biological Chemistry. 274 (8): 4489-92. doi:10.1074/jbc.274.8.4489. PMID9988678.
^ abWong L, Deb TB, Thompson SA, Wells A, Johnson GR (March 1999). "A differential requirement for the COOH-terminal region of the epidermal growth factor (EGF) receptor in amphiregulin and EGF mitogenic signaling". The Journal of Biological Chemistry. 274 (13): 8900-9. doi:10.1074/jbc.274.13.8900. PMID10085134.
^Stortelers C, Souriau C, van Liempt E, van de Poll ML, van Zoelen EJ (July 2002). "Role of the N-terminus of epidermal growth factor in ErbB-2/ErbB-3 binding studied by phage display". Biochemistry. 41 (27): 8732-41. doi:10.1021/bi025878c. PMID12093292.
^ abDaly RJ, Sanderson GM, Janes PW, Sutherland RL (May 1996). "Cloning and characterization of GRB14, a novel member of the GRB7 gene family". The Journal of Biological Chemistry. 271 (21): 12502-10. doi:10.1074/jbc.271.21.12502. PMID8647858.
^ abcBraverman LE, Quilliam LA (February 1999). "Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck". The Journal of Biological Chemistry. 274 (9): 5542-9. doi:10.1074/jbc.274.9.5542. PMID10026169.
^Blagoev B, Kratchmarova I, Ong SE, Nielsen M, Foster LJ, Mann M (March 2003). "A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling". Nature Biotechnology. 21 (3): 315-8. doi:10.1038/nbt790. PMID12577067.
^Okutani T, Okabayashi Y, Kido Y, Sugimoto Y, Sakaguchi K, Matuoka K, Takenawa T, Kasuga M (December 1994). "Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cells". The Journal of Biological Chemistry. 269 (49): 31310-4. PMID7527043.
^Tortora G, Damiano V, Bianco C, Baldassarre G, Bianco AR, Lanfrancone L, Pelicci PG, Ciardiello F (February 1997). "The RIalpha subunit of protein kinase A (PKA) binds to Grb2 and allows PKA interaction with the activated EGF-receptor". Oncogene. 14 (8): 923-8. doi:10.1038/sj.onc.1200906. PMID9050991.
^ abBuday L, Egan SE, Rodriguez Viciana P, Cantrell DA, Downward J (March 1994). "A complex of Grb2 adaptor protein, Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated in ras activation in T cells". The Journal of Biological Chemistry. 269 (12): 9019-23. PMID7510700.
^Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J (August 1992). "The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling". Cell. 70 (3): 431-42. doi:10.1016/0092-8674(92)90167-B. PMID1322798.
^ abcdeOlayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE (June 1999). "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases". The Journal of Biological Chemistry. 274 (24): 17209-18. doi:10.1074/jbc.274.24.17209. PMID10358079.
^Schroeder JA, Thompson MC, Gardner MM, Gendler SJ (April 2001). "Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland". The Journal of Biological Chemistry. 276 (16): 13057-64. doi:10.1074/jbc.M011248200. PMID11278868.
^Li Y, Ren J, Yu W, Li Q, Kuwahara H, Yin L, Carraway KL, Kufe D (September 2001). "The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin". The Journal of Biological Chemistry. 276 (38): 35239-42. doi:10.1074/jbc.C100359200. PMID11483589.
^Tang J, Feng GS, Li W (October 1997). "Induced direct binding of the adapter protein Nck to the GTPase-activating protein-associated protein p62 by epidermal growth factor". Oncogene. 15 (15): 1823-32. doi:10.1038/sj.onc.1201351. PMID9362449.
^Chen M, She H, Davis EM, Spicer CM, Kim L, Ren R, Le Beau MM, Li W (September 1998). "Identification of Nck family genes, chromosomal localization, expression, and signaling specificity". The Journal of Biological Chemistry. 273 (39): 25171-8. doi:10.1074/jbc.273.39.25171. PMID9737977.
^Sun J, Nanjundan M, Pike LJ, Wiedmer T, Sims PJ (May 2002). "Plasma membrane phospholipid scramblase 1 is enriched in lipid rafts and interacts with the epidermal growth factor receptor". Biochemistry. 41 (20): 6338-45. doi:10.1021/bi025610l. PMID12009895.
^Sarmiento M, Puius YA, Vetter SW, Keng YF, Wu L, Zhao Y, Lawrence DS, Almo SC, Zhang ZY (July 2000). "Structural basis of plasticity in protein tyrosine phosphatase 1B substrate recognition". Biochemistry. 39 (28): 8171-9. doi:10.1021/bi000319w. PMID10889023.
^Zhang ZY, Walsh AB, Wu L, McNamara DJ, Dobrusin EM, Miller WT (March 1996). "Determinants of substrate recognition in the protein-tyrosine phosphatase, PTP1". The Journal of Biological Chemistry. 271 (10): 5386-92. doi:10.1074/jbc.271.10.5386. PMID8621392.
^ abTomic S, Greiser U, Lammers R, Kharitonenkov A, Imyanitov E, Ullrich A, Böhmer FD (September 1995). "Association of SH2 domain protein tyrosine phosphatases with the epidermal growth factor receptor in human tumor cells. Phosphatidic acid activates receptor dephosphorylation by PTP1C". The Journal of Biological Chemistry. 270 (36): 21277-84. doi:10.1074/jbc.270.36.21277. PMID7673163.
^Keilhack H, Tenev T, Nyakatura E, Godovac-Zimmermann J, Nielsen L, Seedorf K, Böhmer FD (September 1998). "Phosphotyrosine 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to the epidermal growth factor receptor and attenuation of receptor signaling". The Journal of Biological Chemistry. 273 (38): 24839-46. doi:10.1074/jbc.273.38.24839. PMID9733788.
^Lu Y, Brush J, Stewart TA (April 1999). "NSP1 defines a novel family of adaptor proteins linking integrin and tyrosine kinase receptors to the c-Jun N-terminal kinase/stress-activated protein kinase signaling pathway". The Journal of Biological Chemistry. 274 (15): 10047-52. doi:10.1074/jbc.274.15.10047. PMID10187783.
^Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I (March 2002). "Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors". Nature. 416 (6877): 183-7. doi:10.1038/416183a. PMID11894095.
^Szymkiewicz I, Kowanetz K, Soubeyran P, Dinarina A, Lipkowitz S, Dikic I (October 2002). "CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases". The Journal of Biological Chemistry. 277 (42): 39666-72. doi:10.1074/jbc.M205535200. PMID12177062.
^Sakaguchi K, Okabayashi Y, Kido Y, Kimura S, Matsumura Y, Inushima K, Kasuga M (April 1998). "Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells". Molecular Endocrinology. 12 (4): 536-43. doi:10.1210/me.12.4.536. PMID9544989.
^Keely SJ, Calandrella SO, Barrett KE (April 2000). "Carbachol-stimulated transactivation of epidermal growth factor receptor and mitogen-activated protein kinase in T(84) cells is mediated by intracellular Ca2+, PYK-2, and p60(src)". The Journal of Biological Chemistry. 275 (17): 12619-25. doi:10.1074/jbc.275.17.12619. PMID10777553.
^Sato K, Kimoto M, Kakumoto M, Horiuchi D, Iwasaki T, Tokmakov AA, Fukami Y (September 2000). "Adaptor protein Shc undergoes translocation and mediates up-regulation of the tyrosine kinase c-Src in EGF-stimulated A431 cells". Genes to Cells. 5 (9): 749-64. doi:10.1046/j.1365-2443.2000.00358.x. PMID10971656.
^Xia L, Wang L, Chung AS, Ivanov SS, Ling MY, Dragoi AM, Platt A, Gilmer TM, Fu XY, Chin YE (August 2002). "Identification of both positive and negative domains within the epidermal growth factor receptor COOH-terminal region for signal transducer and activator of transcription (STAT) activation". The Journal of Biological Chemistry. 277 (34): 30716-23. doi:10.1074/jbc.M202823200. PMID12070153.
^Sehat B, Andersson S, Girnita L, Larsson O (July 2008). "Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis". Cancer Research. 68 (14): 5669-77. doi:10.1158/0008-5472.CAN-07-6364. PMID18632619.
Filardo EJ (February 2002). "Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer". The Journal of Steroid Biochemistry and Molecular Biology. 80 (2): 231-8. doi:10.1016/S0960-0760(01)00190-X. PMID11897506.
Anderson NL, Anderson NG (November 2002). "The human plasma proteome: history, character, and diagnostic prospects". Molecular & Cellular Proteomics. 1 (11): 845-67. doi:10.1074/mcp.R200007-MCP200. PMID12488461.
Kari C, Chan TO, Rocha de Quadros M, Rodeck U (January 2003). "Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage". Cancer Research. 63 (1): 1-5. PMID12517767.
Carlsson J, Ren ZP, Wester K, Sundberg AL, Heldin NE, Hesselager G, Persson M, Gedda L, Tolmachev V, Lundqvist H, Blomquist E, Nistér M (March 2006). "Planning for intracavitary anti-EGFR radionuclide therapy of gliomas. Literature review and data on EGFR expression". Journal of Neuro-Oncology. 77 (1): 33-45. doi:10.1007/s11060-005-7410-z. PMID16200342.
Scartozzi M, Pierantoni C, Berardi R, Antognoli S, Bearzi I, Cascinu S (April 2006). "Epidermal growth factor receptor: a promising therapeutic target for colorectal cancer". Analytical and Quantitative Cytology and Histology. 28 (2): 61-8. PMID16637508.
Prudkin L, Wistuba II (October 2006). "Epidermal growth factor receptor abnormalities in lung cancer. Pathogenetic and clinical implications". Annals of Diagnostic Pathology. 10 (5): 306-15. doi:10.1016/j.anndiagpath.2006.06.011. PMID16979526.