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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.

References

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^ Sehat, Bita; Andersson Sandra, Girnita Leonard, Larsson Olle (Jul. 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 Res. (United States) 68 (14): 566977. doi:10.1158/0008-5472.CAN-07-6364. PMID 18632619. 

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. 

v  d  e

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  

v  d  e

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

v  d  e

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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