The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a
transmembrane protein that is a
receptor for members of the
epidermal growth factor
Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds.
EGF was originally de ...
family (EGF family) of
extracellular protein
ligands.
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/neu (ErbB-2),
Her 3 (ErbB-3) and
Her 4 (ErbB-4). In many cancer types, mutations affecting EGFR expression or activity could result in
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
.
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 factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for r ...
s.
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.
Function
Epidermal growth factor receptor (EGFR) is a
transmembrane protein that is activated by binding of its specific
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
s, including
epidermal growth factor
Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds.
EGF was originally de ...
and
transforming growth factor α (TGFα). ErbB2 has no known direct activating
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
, 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 domain
The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains allow proteins containing those domains to dock to phosph ...
s. These downstream signaling proteins initiate several
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
cascades, principally the
MAPK,
Akt and
JNK pathways, leading to
DNA synthesis and cell proliferation.
Such proteins modulate phenotypes such as
cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular dire ...
,
adhesion, and
proliferation
Proliferation may refer to:
Weapons
*Nuclear proliferation, the spread of nuclear weapons, material, and technology
*Chemical weapon proliferation, the spread of chemical weapons, material, and technology
* Small arms proliferation, the spread of ...
. 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,
and
agonists of the EGFR such as
amphiregulin,
TGF-α
Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene. As a member of the epidermal growth factor (EGF) family, TGF-α is a mitogenic polypeptide. The protein becomes activated when binding to recepto ...
, and heregulin induce both ductal and
lobuloalveolar development even in the absence of
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal a ...
and
progesterone.
Role in human disease
Cancer
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s that lead to EGFR overexpression (known as upregulation or amplification) have been associated with a number of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
s, including
adenocarcinoma of the lung (40% of cases),
anal cancers,
glioblastoma (50%) and
epithelian tumors of the head and neck (80–100%). These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division.
In
glioblastoma a 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.
Inflammatory disease
Aberrant EGFR signaling has been implicated in psoriasis, eczema and atherosclerosis.
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 diarrhoea, abnormalities of hair growth, breathing difficulties and electrolyte imbalances.
Wound healing and fibrosis
EGFR has been shown to play a critical role in
TGF-beta1 dependent
fibroblast
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of ...
to
myofibroblast differentiation.
Aberrant persistence of
myofibroblasts within tissues can lead to progressive tissue
fibrosis, impairing tissue or organ function (e.g. skin
hypertrophic or
keloid scars,
liver cirrhosis,
myocardial fibrosis,
chronic kidney disease
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, ...
).
Medical applications
Drug target
The identification of EGFR as an
oncogene has led to the development of anticancer therapeutics directed against EGFR (called "EGFR inhibitors", EGFRi), including
gefitinib,
erlotinib,
afatinib
Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.
It is mainly used to tr ...
,
brigatinib and
icotinib
Icotinib (trade name Conmana) is a highly selective, first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Icotinib is approved for use in China as first-line monotherapy in patients with non-small-cell lung can ...
for lung cancer, and
cetuximab for
colon cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...
. More recently AstraZeneca has developed
Osimertinib, a third generation tyrosine kinase inhibitor.
Many therapeutic approaches are aimed at the EGFR. Cetuximab and
panitumumab are examples of
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ...
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
Zalutumumab (proposed trade name HuMax-EGFR) is a fully human IgG1 monoclonal antibody (mAb) directed towards the epidermal growth factor receptor (EGFR). It is a product developed by Genmab in Utrecht, the Netherlands. Specifically, zalutumumab ...
,
nimotuzumab, and
matuzumab
Matuzumab (formerly EMD 72000) is a humanized monoclonal antibody for the treatment of cancer. It binds to the epidermal growth factor receptor (EGFR) with high affinity. The mouse monoclonal antibody (mAb425) from which matuzumab was developed a ...
. 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
In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...
inhibitors.
CimaVax-EGF CimaVax-EGF is a vaccine used to treat cancer, specifically non-small-cell lung carcinoma (NSCLC). CIMAvax-EGF is composed of recombinant human epidermal growth factor (EGF) conjugated to a protein carrier.
The vaccine was developed by the Cen ...
, an active
vaccine
A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified.[ ...]
targeting EGF as the major
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
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
An adverse effect is an undesired harmful effect resulting from a Pharmaceutical drug, medication or other Surgery#Definitions, intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main ...
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 VeriStrat is a test developed to evaluate patient prognosis and, additionally, predict benefit from cancer treatment by EGFR inhibitors. It is a serum/plasma proteomic test developed using matrix-assisted laser desorption/ionization (MALDI) mass spe ...
.
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.
It has been proposed that certain computed tomography findings such as ground-glass opacities, air bronchogram, spiculated margins, vascular convergence, and pleural retraction can predict the presence of EGFR mutation in patients with non-small cell lung cancer.
Interactions
Epidermal growth factor receptor has been shown to
interact with:
*
AR,
*
ARF4,
*
CAV1,
*
CAV3,
[
* CBL,]
* CBLB,[
* CBLC,]
* CD44,
* CDC25A,
* CRK
Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the ''CRK'' gene.
The CRK protein participates in the Reelin signaling cascade downstream of DAB1.
Function
Adapter molecule crk is a member of ...
,
* CTNNB1,
* DCN,
* EGF EGF may refer to:
* E.G.F., a Gabonese company
* East Grand Forks, Minnesota, a city
* East Garforth railway station in England
* Epidermal growth factor
* Equity Group Foundation, a Kenyan charity
* European Gendarmerie Force, a military unit of ...
,
* GRB14,
* Grb2,
* JAK2,
* MUC1,
* NCK1
Cytoplasmic protein NCK1 is a protein that in humans is encoded by the ''NCK1'' gene.
Gene
The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated from ...
,
* NCK2
* PKC alpha,
* PLCG1,
* PLSCR1,
* PTPN1
Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the ''PTPN1'' gene. PTP1B i ...
,
* PTPN11,
* PTPN6,
* PTPRK,
* SH2D3A,
* SH3KBP1,
* SHC1,
* SOS1,
* Src,
* STAT1,
* STAT3,
* STAT5A,[
* UBC,] and
* WAS
Was or WAS may refer to:
* ''Was'', a past-tense form of the English copular verb ''to be''
People
* David Was (born c. 1952), the stage name of multi-instrumentalist and songwriter David Weiss
* Don Was (born 1952), the stage name of bass gui ...
,
* PAR2.
In fruitflies, the epidermal growth factor receptor interacts with Spitz.
References
Further reading
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External links
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{{DEFAULTSORT:Epidermal Growth Factor Receptor
Tyrosine kinase receptors
Oncogenes