Epidermal growth factor receptor

Epidermal growth factor receptor

Extracellular domain of Epidermal growth factor receptor in complex with EGF. PDB 1nql[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols EGFR ; ERBB; ERBB1; HER1; NISBD2; PIG61; mENA
External IDs OMIM: 131550 MGI: 95294 HomoloGene: 74545 ChEMBL: 203 GeneCards: EGFR Gene
EC number 2.7.10.1
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 1956 13649
Ensembl ENSG00000146648 ENSMUSG00000020122
UniProt P00533 Q01279
RefSeq (mRNA) NM_005228 NM_007912
RefSeq (protein) NP_005219 NP_031938
Location (UCSC) Chr 7:
55.02 – 55.26 Mb		 Chr 11:
16.75 – 16.92 Mb
PubMed search

The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands.[2]

The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). Mutations affecting EGFR expression or activity could result in cancer.[3]

Epidermal growth factor and its receptor was discovered by Stanley Cohen of Vanderbilt University. Cohen shared the 1986 Nobel Prize in Medicine with Rita Levi-Montalcini for their discovery of growth factors.

Function

EGFR signaling cascades
Diagram of the EGF receptor highlighting important domains

Epidermal growth factor receptor (EGFR) exists on the cell surface and is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor α (TGFα) (note, a full list of the ligands able to activate EGFR and other members of the ErbB family is given in the ErbB article). 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[4] – 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 diagram to the left.[5] 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.[6] 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.

Biological roles

The EGFR is essential for ductal development of the mammary glands,[7][8][9] and agonists of the EGFR such as amphiregulin, TGF-α, and heregulin induce both ductal and lobuloalveolar development even in the absence of estrogen and progesterone.[10][11]

Role in human disease

Cancer

Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including lung cancer, anal cancers[12] and glioblastoma multiforme. These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division.[13] In glioblastoma a more or less specific mutation of EGFR, called EGFRvIII is often observed.[14] Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.

Inflammatory disease

Aberrant EGFR signaling has been implicated in psoriasis, eczema and atherosclerosis.[15][16] However, its exact roles in these conditions are ill-defined.

Monogenic disease

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 diarrhea, abnormalities of hair growth, breathing difficulties and electrolyte imbalances.[17]

Medical applications

Main article: EGFR inhibitors

Cancer treatment

The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR (called "EGFR inhibitors"), including gefitinib,[18] erlotinib, afatinib, brigatinib and icotinib[19] for lung cancer, and cetuximab for colon cancer.

Many therapeutic approaches are aimed at the EGFR. Cetuximab and panitumumab are examples of monoclonal antibody inhibitors. However the former is of the IgG1 type, the latter of the IgG2 type; consequences on antibody-dependent cellular cytotoxicity can be quite different.[20] Other monoclonals in clinical development are zalutumumab, nimotuzumab, and matuzumab. The monoclonal antibodies block the extracellular ligand binding domain. With the binding site blocked, signal molecules can no longer attach there and activate the tyrosine kinase.

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;[21] 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.[22]

There are several quantitative methods available that use protein phosphorylation detection to identify EGFR family inhibitors.[23]

New drugs such as 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.[24]

However, many patients develop resistance. Two primary sources of resistance are the T790M Mutation and MET oncogene.[24] 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.[25] In 10% to 15% of patients the effects can be serious and require treatment.[26][27]

Some tests are aiming at predicting benefit from EGFR treatment, as Veristrat.[28]

Laboratory research using genetically engineered stem cells to target EGFR in mice was reported in 2014 to show promise.[29]

Interactions

Epidermal growth factor receptor has been shown to interact with:

References

  1. ↑ Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA (2003). "EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization". Mol. Cell 11 (2): 507–17. doi:10.1016/S1097-2765(03)00047-9. PMID 12620237.
  2. ↑ Herbst RS (2004). "Review of epidermal growth factor receptor biology". Int. J. Radiat. Oncol. Biol. Phys. 59 (2 Suppl): 21–6. doi:10.1016/j.ijrobp.2003.11.041. PMID 15142631.
  3. ↑ Zhang H, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, Greene MI (August 2007). "ErbB receptors: from oncogenes to targeted cancer therapies". J. Clin. Invest. 117 (8): 2051–8. doi:10.1172/JCI32278. PMC 1934579. PMID 17671639.
  4. ↑ Yosef Yarden and Joseph Schlessinger (1987). "Epidermal Growth-Factor Induces Rapid, Reversible Aggregation of the Purified Epidermal Growth-Factor Receptor". Biochemistry 26 (5): 1443–1451. doi:10.1021/bi00379a035. PMID 3494473.
  5. ↑ Downward J, Parker P, Waterfield MD (1984). "Autophosphorylation sites on the epidermal growth factor receptor". Nature 311 (5985): 483–5. doi:10.1038/311483a0. PMID 6090945.
  6. ↑ Oda K, Matsuoka Y, Funahashi A, Kitano H (2005). "A comprehensive pathway map of epidermal growth factor receptor signaling". Mol. Syst. Biol. 1 (1): 2005.0010. doi:10.1038/msb4100014. PMC 1681468. PMID 16729045.
  7. ↑ Sebastian J, Richards RG, Walker MP, Wiesen JF, Werb Z, Derynck R, Hom YK, Cunha GR, DiAugustine RP (1998). "Activation and function of the epidermal growth factor receptor and erbB-2 during mammary gland morphogenesis". Cell Growth Differ. 9 (9): 777–85. PMID 9751121.
  8. ↑ McBryan J, Howlin J, Napoletano S, Martin F (2008). "Amphiregulin: role in mammary gland development and breast cancer". J Mammary Gland Biol Neoplasia 13 (2): 159–69. doi:10.1007/s10911-008-9075-7. PMID 18398673.
  9. ↑ Sternlicht MD, Sunnarborg SW (2008). "The ADAM17-amphiregulin-EGFR axis in mammary development and cancer". J Mammary Gland Biol Neoplasia 13 (2): 181–94. doi:10.1007/s10911-008-9084-6. PMC 2723838. PMID 18470483.
  10. ↑ Kenney NJ, Bowman A, Korach KS, Barrett JC, Salomon DS (2003). "Effect of exogenous epidermal-like growth factors on mammary gland development and differentiation in the estrogen receptor-alpha knockout (ERKO) mouse". Breast Cancer Res. Treat. 79 (2): 161–73. doi:10.1023/a:1023938510508. PMID 12825851.
  11. ↑ Kenney NJ, Smith GH, Rosenberg K, Cutler ML, Dickson RB (1996). "Induction of ductal morphogenesis and lobular hyperplasia by amphiregulin in the mouse mammary gland". Cell Growth Differ. 7 (12): 1769–81. PMID 8959346.
  12. ↑ Walker F, Abramowitz L, Benabderrahmane D, Duval X, Descatoire V, Hénin D, Lehy T, Aparicio T (November 2009). "Growth factor receptor expression in anal squamous lesions: modifications associated with oncogenic human papillomavirus and human immunodeficiency virus". Hum. Pathol. 40 (11): 1517–27. doi:10.1016/j.humpath.2009.05.010. PMID 19716155.
  13. ↑ Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (May 2004). "Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib". N. Engl. J. Med. 350 (21): 2129–39. doi:10.1056/NEJMoa040938. PMID 15118073.
  14. ↑ Kuan CT, Wikstrand CJ, Bigner DD (June 2001). "EGF mutant receptor vIII as a molecular target in cancer therapy". Endocr. Relat. Cancer 8 (2): 83–96. doi:10.1677/erc.0.0080083. PMID 11397666.
  15. ↑ Jost M, Kari C, Rodeck U (2000). "The EGF receptor - an essential regulator of multiple epidermal functions". Eur J Dermatol 10 (7): 505–10. PMID 11056418.
  16. ↑ Dreux AC, Lamb DJ, Modjtahedi H, Ferns GA (2006). "The epidermal growth factor receptors and their family of ligands: their putative role in atherogenesis". Atherosclerosis 186 (1): 38–53. doi:10.1016/j.atherosclerosis.2005.06.038. PMID 16076471.
  17. ↑ Campbell P, Morton P, Takeichi T, Salam A, Roberts N, Proudfoot LE, Mellerio JE, Aminu K, Wellington C, Patil SN, Akiyama M, Liu L, McMillan JR, Aristodemou S, Ishida-Yamamoto A, Abdul-Wahab A, Petrof G, Fong K, Harnchoowong S, Stone K, Harper JI, McLean WH, Simpson MA, Parsons M, McGrath JA (2014). "Epithelial Inflammation Resulting from an Inherited Loss-of-Function Mutation in EGFR". J. Invest. Dermatol. 134 (10): 2570–2578. doi:10.1038/jid.2014.164. PMID 24691054.
  18. ↑ 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. PMID 15118125.
  19. ↑ Liang, Wenhua; Wu, Xuan; Fang, Wenfeng; Zhao, Yuanyuan; Yang, Yunpeng; Hu, Zhihuang; Xue, Cong; Zhang, Jing; Zhang, Jianwei; Ma, Yuxiang; Zhou, Ting; Yan, Yue; Hou, Xue; Qin, Tao; Dinglin, Xiaoxiao; Tian, Ying; Huang, Peiyu; Huang, Yan; Zhao, Hongyun; Zhang, Li; Ganti, Apar Kishor (12 February 2014). "Network Meta-Analysis of Erlotinib, Gefitinib, Afatinib and Icotinib in Patients with Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations". PLoS ONE 9 (2): e85245. doi:10.1371/journal.pone.0085245.
  20. ↑ Yan L, Beckman RA (October 2005). "Pharmacogenetics and pharmacogenomics in oncology therapeutic antibody development". BioTechniques 39 (4): 565–8. doi:10.2144/000112043. PMID 16235569.
  21. ↑ Rodríguez, Pedro C; Rodríguez, Gryssell; González, Giselaa; Lage, Agustín (Winter 2010). "Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy". MEDICC Rev 12 (1): 17–23. PMID 20387330. Retrieved 13 May 2015.
  22. ↑ Patel, Neel (11 May 2015). "Cuba Has a Lung Cancer Vaccine—And America Wants It". Wired. Retrieved 13 May 2015.
  23. ↑ Olive DM (October 2004). "Quantitative methods for the analysis of protein phosphorylation in drug development". Expert Rev Proteomics 1 (3): 327–41. doi:10.1586/14789450.1.3.327. PMID 15966829.
  24. 1 2 Jackman DM, Miller VA, Cioffredi LA, Yeap BY, Jänne PA, Riely GJ, Ruiz MG, Giaccone G, Sequist LV, Johnson BE (August 2009). "Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials". Clin. Cancer Res. 15 (16): 5267–73. doi:10.1158/1078-0432.CCR-09-0888. PMC 3219530. PMID 19671843.
  25. ↑ Liu HB, Wu Y, Lv TF, Yao YW, Xiao YY, Yuan DM, Song Y (2013). "Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis". PLoS ONE 8 (1): e55128. doi:10.1371/journal.pone.0055128. PMC 3559430. PMID 23383079.
  26. ↑ Gerber PA, Meller S, Eames T, Buhren BA, Schrumpf H, Hetzer S, Ehmann LM, Budach W, Bölke E, Matuschek C, Wollenberg A, Homey B (2012). "Management of EGFR-inhibitor associated rash: a retrospective study in 49 patients". Eur. J. Med. Res. 17 (1): 4. doi:10.1186/2047-783X-17-4. PMC 3351712. PMID 22472354.
  27. ↑ Lacouture ME (2006). "Mechanisms of cutaneous toxicities to EGFR inhibitors". Nat. Rev. Cancer 6 (10): 803–12. doi:10.1038/nrc1970. PMID 16990857.
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  34. 1 2 Tvorogov D, Carpenter Graham (Jul 2002). "EGF-dependent association of phospholipase C-gamma1 with c-Cbl". Exp. Cell Res. 277 (1): 86–94. doi:10.1006/excr.2002.5545. PMID 12061819.
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