Pci Exp
Epidermal Growth Factor Receptor
Function
EGFR (epidermal growth factor receptor) exists on the cell surface and is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor (TGF) (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 – although there is some evidence that preformed inactive dimers may also exist before ligand binding[citation needed]. 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[citation needed].
Diagram of the EGF receptor highlighting important domains
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. 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.
Clinical applications
Mutations that lead to EGFR over[removed]known as upregulation) or overactivity have been associated with a number of cancers, including lung cancer, anal cancers and glioblastoma multiforme. In this latter case a more or less specific mutation of EGFR, called EGFRvIII is often observed. Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.
Mutations involving EGFR could lead to its constant activation which could result in uncontrolled cell division a predisposition for cancer. Consequently, mutations of EGFR have been identified in several types of cancer, and it is the target of an expanding class of anticancer therapies.
The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including gefitinib and erlotinib 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. Other monoclonals in clinical development are zalutumumab, nimotuzumab, and matuzumab. Gefitinib, erlotinib, and lapatinib (mixed EGFR and ERBB2 inhibitor) are examples of small molecule kinase inhibitors. 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. There are several quantitative methods available that use protein phosphorylation detection to identify EGFR family inhibitors.
Efficient conversion of strongly absorbed light by plasmonic gold nanoparticles to heat energy and their easy bioconjugation suggest their use as selective photothermal agents in molecular cancer cell targeting. Two oral squamous carcinoma cell lines (HSC 313 and HOC 3 Clone 
and one benign epithelial cell line (HaCaT) were incubated with anti-epithelial growth factor receptor (EGFR) antibody conjugated gold nanoparticles and then exposed to continuous visible argon ion laser at 514 nm. It is found that the malignant cells require less than half the laser energy to be killed than the benign cells after incubation with anti-EGFR antibody conjugated Au nanoparticles. No photothermal destruction is observed for all types of cells in the absence of nanoparticles at four times energy required to kill the malignant cells with anti-EGFR/Au conjugates bonded. Au nanoparticles thus offer a novel class of selective photothermal agents using a CW laser at low powers.
In July 2007 it was discovered that the blood clotting protein fibrinogen activates EGFR, thereby blocking regrowth of injured neuronal cells in the spine. Other natural inhibitors include potato carboxypeptidase inhibitor (PCI), which contains a small cysteine-rich module, called a T-knot scaffold, that is shared by several different protein families, including the EGF family. Structural similarities with these factors can explain the antagonistic effect of PCI.
EGFR and Lung Cancer
New drugs such as Tarceva directly target the EGFR. Patients have been divided into EGFR positive and negative, based upon whether a tissue test shows a mutation. EGFR positive patients have shown an impressive 60% response rate which exceeds the response rate for conventional chemotherapy.[citation needed]
Interactions
Epidermal growth factor receptor has been shown to interact with PLCG1, NCK1, Janus kinase 2, CDC25A, MUC1, Caveolin 1, STAT5A, PTPN1, CRK, SHC1, Beta-catenin, PTPN11, PTPN6, STAT1, CBLC, Src, Androgen receptor, STAT3, GRB14, Grb2, PLSCR1, Wiskott-Aldrich syndrome protein, SH2D3A, Epidermal growth factor, CBLB, Cbl gene, ARF4, PKC alpha, SOS1, SH3KBP1, Caveolin 3, Decorin, NCK2 and Ubiquitin C.
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External links
MeSH Epidermal Growth Factor Receptor
Further reading
Carpenter G (1987). “Receptors for epidermal growth factor and other polypeptide mitogens”. Annu. Rev. Biochem. 56: 881914. doi:10.1146/annurev.bi.56.070187.004313. PMID 3039909.
Boonstra J, Rijken P, Humbel B, et al. (1995). “The epidermal growth factor”. Cell Biol. Int. 19 (5): 41330. doi:10.1006/cbir.1995.1086. PMID 7640657.
Carpenter G (2000). “The EGF receptor: a nexus for trafficking and signaling”. Bioessays 22 (8): 697707. doi:10.1002/1521-1878(200008)22:8<697::AID-BIES3>3.0.CO;2-1. PMID 10918300.
Filardo EJ (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”. J. Steroid Biochem. Mol. Biol. 80 (2): 2318. doi:10.1016/S0960-0760(01)00190-X. PMID 11897506.
Tiganis T (2002). “Protein tyrosine phosphatases: dephosphorylating the epidermal growth factor receptor”. IUBMB Life 53 (1): 314. doi:10.1080/15216540210811. PMID 12018405.
Di Fiore PP, Scita G (2002). “Eps8 in the midst of GTPases”. Int. J. Biochem. Cell Biol. 34 (10): 117883. doi:10.1016/S1357-2725(02)00064-X. PMID 12127568.
Benaim G, Villalobo A (2002). “Phosphorylation of calmodulin. Functional implications”. Eur. J. Biochem. 269 (15): 361931. doi:10.1046/j.1432-1033.2002.03038.x. PMID 12153558.
Leu TH, Maa MC (2004). “Functional implication of the interaction between EGF receptor and c-Src”. Front. Biosci. 8: s2838. doi:10.2741/980. PMID 12456372.
Anderson NL, Anderson NG (2003). “The human plasma proteome: history, character, and diagnostic prospects”. Mol. Cell Proteomics 1 (11): 84567. PMID 12488461.
Kari C, Chan TO, Rocha de Quadros M, Rodeck U (2003). “Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage”. Cancer Res. 63 (1): 15. PMID 12517767.
Bonaccorsi L, Muratori M, Carloni V, et al. (2003). “Androgen receptor and prostate cancer invasion”. Int. J. Androl. 26 (1): 215. doi:10.1046/j.1365-2605.2003.00375.x. PMID 12534934.
Reiter JL, Maihle NJ (2003). “Characterization and expression of novel 60-kDa and 110-kDa EGFR isoforms in human placenta”. Ann. N. Y. Acad. Sci. 995: 3947. PMID 12814937.
Adams TE, McKern NM, Ward CW (2005). “Signalling by the type 1 insulin-like growth factor receptor: interplay with the epidermal growth factor receptor”. Growth Factors 22 (2): 8995. PMID 15253384.
Ferguson KM (2005). “Active and inactive conformations of the epidermal growth factor receptor”. Biochem. Soc. Trans. 32 (Pt 5): 7425. doi:10.1042/BST0320742. PMID 15494003.
Chao C, Hellmich MR (2005). “Bi-directional signaling between gastrointestinal peptide hormone receptors and epidermal growth factor receptor”. Growth Factors 22 (4): 2618. doi:10.1080/08977190412331286900. PMID 15621729.
Carlsson J, Ren ZP, Wester K, et al. (2006). “Planning for intracavitary anti-EGFR radionuclide therapy of gliomas. Literature review and data on EGFR expression”. J. Neurooncol. 77 (1): 3345. doi:10.1007/s11060-005-7410-z. PMID 16200342.
Scartozzi M, Pierantoni C, Berardi R, et al. (2006). “Epidermal growth factor receptor: a promising therapeutic target for colorectal cancer”. Anal. Quant. Cytol. Histol. 28 (2): 618. PMID 16637508.
Prudkin L, Wistuba II (2006). “Epidermal growth factor receptor abnormalities in lung cancer. Pathogenetic and clinical implications”. Annals of diagnostic pathology 10 (5): 30615. doi:10.1016/j.anndiagpath.2006.06.011. PMID 16979526.
Ahmed SM, Salgia R (2007). “Epidermal growth factor receptor mutations and susceptibility to targeted therapy in lung cancer”. Respirology 11 (6): 68792. doi:10.1111/j.1440-1843.2006.00887.x. PMID 17052295.
Zhang X, Chang A (2007). “Somatic mutations of the epidermal growth factor receptor and non-small-cell lung cancer”. J. Med. Genet. 44 (3): 16672. doi:10.1136/jmg.2006.046102. PMID 17158592.
Cohenuram M, Saif MW (2007). “Epidermal growth factor receptor inhibition strategies in pancreatic cancer: past, present and the future”. JOP 8 (1): 415. PMID 17228128.
Mellinghoff IK, Cloughesy TF, Mischel PS (2007). “PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors”. Clin. Cancer Res. 13 (2 Pt 1): 37881. doi:10.1158/1078-0432.CCR-06-1992. PMID 17255257.
Nakamura JL (2007). “The epidermal growth factor receptor in malignant gliomas: pathogenesis and therapeutic implications”. Expert Opin. Ther. Targets 11 (4): 46372. doi:10.1517/14728222.11.4.463. PMID 17373877.
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PDB Gallery
1ivo: Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular Domains.
1m14: Tyrosine Kinase Domain from Epidermal Growth Factor Receptor
1m17: Epidermal Growth Factor Receptor tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib
1mox: Crystal Structure of Human Epidermal Growth Factor Receptor (residues 1-501) in complex with TGF-alpha
1nql: Structure of the extracellular domain of human epidermal growth factor (EGF) receptor in an inactive (low pH) complex with EGF.
1xkk: EGFR kinase domain complexed with a quinazoline inhibitor- GW572016
1yy9: Structure of the extracellular domain of the epidermal growth factor receptor in complex with the Fab fragment of cetuximab/Erbitux/IMC-C225
1z9i: A Structural Model for the Membrane-Bound Form of the Juxtamembrane Domain of the Epidermal Growth Factor Receptor
2gs2: Crystal Structure of the active EGFR kinase domain
2gs6: Crystal Structure of the active EGFR kinase domain in complex with an ATP analog-peptide conjugate
2gs7: Crystal Structure of the inactive EGFR kinase domain in complex with AMP-PNP
2itn: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN G719S MUTATION IN COMPLEX WITH AMP-PNP
2ito: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN G719S MUTATION IN COMPLEX WITH IRESSA
2itp: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN G719S MUTATION IN COMPLEX WITH AEE788
2itq: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN G719S MUTATION IN COMPLEX WITH AFN941
2itt: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN L858R MUTATION IN COMPLEX WITH AEE788
2itu: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN L858R MUTATION IN COMPLEX WITH AFN941
2itv: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN L858R MUTATION IN COMPLEX WITH AMP-PNP
2itw: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN IN COMPLEX WITH AFN941
2itx: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN IN COMPLEX WITH AMP-PNP
2ity: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN IN COMPLEX WITH IRESSA
2itz: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN L858R MUTATION IN COMPLEX WITH IRESSA
2j5e: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN IN COMPLEX WITH AN IRREVERSIBLE INHIBITOR 13-JAB
2j5f: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN IN COMPLEX WITH AN IRREVERSIBLE INHIBITOR 34-JAB
2j6m: CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN IN COMPLEX WITH AEE788
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Protein kinases: tyrosine kinases (EC 2.7.10)
Receptor tyrosine kinases (EC 2.7.10.1)
EGF receptor family
EGFR ERBB2 ERBB3 ERBB4
Insulin receptor family
IGF1R INSR INSRR
PDGF receptor family
CSF1R FLT3 KIT PDGFR (PDGFRA, PDGFRB)
FGF receptor family
FGFR1 FGFR2 FGFR3 FGFR4
VEGF receptors family
VEGFR1 VEGFR2 VEGFR3 VEGFR4
HGF receptor family
MET RON
Trk receptor family
NTRK1 NTRK2 NTRK3
EPH receptor family
EPHA1 EPHA2 EPHA3 EPHA4 EPHA5 EPHA6 EPHA7 EPHA8 EPHB1 EPHB2 EPHB3 EPHB4 EPHB5 EPHB6 EPHX
LTK receptor family
LTK ALK
TIE receptor family
TIE TEK
ROR receptor family
ROR1 ROR2
DDR receptor family
DDR1 DDR2
PTK7 receptor family
PTK7
RYK receptor family
RYK
MuSK receptor family
MUSK
ROS receptor family
ROS1
AATYK receptor family
AATYK AATYK2 AATYK3
AXL receptor family
AXL MER TYRO3
RET receptor family
RET
uncatagorised
STYK1
Non-receptor tyrosine kinases (EC 2.7.10.2)
ABL family
ABL1 ARG
ACK family
ACK1 TNK1
CSK family
CSK MATK
FAK family
FAK PYK2
FES family
FES FER
FRK family
FRK BRK SRMS
JAK family
JAK1 JAK2 JAK3 TYK2
SRC-A family
SRC FGR FYN YES1
SRC-B family
BLK HCK LCK LYN
TEC family
TEC BMX BTK ITK TXK
SYK family
SYK ZAP70
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Neoplasm: Oncogenes/Proto-oncogenes
Extracellular/
Growth factor
c-Sis/PDGF
Cell membrane/
receptor/tyrosine kinases
ErbB/c-ErbB (HER2/neu, Her 3) – c-Kit – c-Met – c-Ret – Flt3
Cytoplasm/
Signal transduction
c-Src
MAPK/ERK pathway (c-Ras/HRAS, c-Raf)
Akt/PKB signaling pathway (c-Akt)
Wnt signaling pathway (Beta-catenin)
Nucleus/Transcription factors
AP-1 (c-Fos, c-Jun) – c-Myc – c-Mdm2
Other/ungrouped
c-Bcl-2 – Notch – Stathmin
see also tumor suppressor genes
v d e
Receptors: growth factor receptors
Nerve growth factors
Low affinity/p75 – high affinity Trk (TrkA, TrkB, TrkC) – Ciliary neurotrophic factor
Somatomedin
Insulin-like growth factor 1 – Insulin-like growth factor 2
CSF
Stem cell factor – Erythropoietin
TGF pathway
TGF-beta (1, 2) – Activin (1, 2) – Bone morphogenetic protein (1, 2)
Other
Hepatocyte growth factor – ErbB/Epidermal growth factor – Fibroblast growth factor (1, 2, 3, 4) – Platelet-derived growth factor (A, B) – VEGF (1, 2, 3)
see also growth factors
Categories: Human proteins | Tyrosine kinase receptors | OncogenesHidden categories: All articles with unsourced statements | Articles with unsourced statements from October 2009 | Articles with unsourced statements from December 2009
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