The epidermal growth factor receptor ( EGFR ; ErbB-1 ; HER1 in humans) is a transmembrane receptor protein for family members of the epidermal growth factor (EGF family) of the extracellular protein ligand.
The epidermal growth factor receptor is a member of the ErbB receptor family, a subfamily of four closely related tyrosine kinase receptors: EGFR (ErbB-1), HER2/neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4 ). In many types of cancer, mutations that affect the expression or activity of EGFR can cause cancer.
The 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 the discovery of their growth factor.
Defective signaling from EGFR and other tyrosine kinase receptors in humans is associated with diseases such as Alzheimer's, while over-expression is associated with the development of various tumors. EGFR signal disturbance, either by blocking EGFR binding sites on receptor extracellular domains or by inhibiting intracellular tyrosine kinase activity, can prevent EGFR-expressing tumor growth and improve patient condition.
Video Epidermal growth factor receptor
Function
Epidermal growth factor receptor (EGFR) is a transmembrane protein activated by binding to its specific ligand, including epidermal growth factor and changing growth factor? (TGF?) ErbB2 does not have a known direct activating ligand, and can either be actively implicated or active on heterodimerization with other family members such as EGFR. After activation by the growth factor ligand, EGFR undergoes a transition from an inactive monomer form to an active homodimer. - although there is some evidence that inactivated inactive dimers may also exist before ligand binding. In addition to forming a homodimer after ligand binding, EGFR can pair with other members of the ErbB receptor family, such as ErbB2/Her2/neu, to make activated heterodimers. There is also evidence to suggest that the group of EGFR forms is activated, although it remains unclear whether this clustering is important for activation itself or occurs after the activation of an individual dimer.
EGFR dimerization stimulates intracellular intracellular intracellular protein-tyrosine kinase activity. As a result, the autophosphorylation of some tyrosine residues (Y) in the C-terminal EGFR domain occurs. These include Y992, Y1045, Y1068, Y1148 and Y1173, as shown in the adjacent diagram. This autophosphorylation leads to downstream activation and signaling by some other proteins associated with phosphorylated tyrosine through their own SH2 phosphotyrosine-binding domain. This downstream signaling protein initiates several signal transduction cascades, particularly the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation. Proteins such as modulate phenotypes such as cell migration, adhesion, and proliferation. Receptor activation is important for the innate immune response of human skin. The EGFR kinase domain can also secrete tyrosine residues from other receptors by aggregation, and by itself can be activated in that way.
Maps Epidermal growth factor receptor
Biological role
EGFR is essential for the development of ductal mammary glands, and agonists of EGFR such as amphiregulin, TGF- ?, and heregulin induce both ductal and lobuloalveolar development even in the absence of estrogen and progesterone.
Role in human disease
Cancer
Mutations that cause EGFR overexpression (known as upregulation or amplification) have been associated with a number of cancers, including pulmonary squamous cell carcinoma (80% of cases), anal cancer, glioblastoma (50%) and epithelial tumors of the head and neck (80-100%). Somatic mutations involving EGFR cause constant activation, resulting in uncontrolled cell division. In glioblastoma, a specific mutation of EGFR, called EGFRvIII, is often observed. Mutations, amplification or mismanagement of EGFR or family members are involved in about 30% of all epithelial cancers.
Inflammatory diseases
Distorted EGFR signaling has been involved in psoriasis, eczema and atherosclerosis. However, his exact role under these conditions is unclear.
Monogenic Disease
A single child who exhibits multi-organ epithelial inflammation is found to have lost the function of homozygous mutations in the EGFR gene. The pathogenicity of EGFR mutations is supported by in vitro experiments and functional analysis of skin biopsies. Its severe phenotype reflects many of the previous research findings into the EGFR function. Clinical features include papulopustular rash, dry skin, chronic diarrhea, hair growth abnormalities, difficulty breathing and electrolyte imbalances.
Wound healing and fibrosis
EGFR has been shown to play an important role in TGF-beta1 dependent fibroblasts for myofibroblast differentiation. Persistence deviating from myofibroblasts in the tissues can lead to progressive tissue fibrosis, damaging tissue or organ function (eg hypertrophic or keloid scar skin, liver cirrhosis, myocardial fibrosis, chronic kidney disease).
Medical applications
Drug target
Identification of EGFR as oncogenes has led to the development of anticancer therapy directed against EGFR (called "EGFR inhibitors"), including gefitinib, erlotinib, afatinib, brigatinib and icotinib for lung cancer, and cetuximab for colon cancer. Recently AstraZeneca has developed Osimertinib, a third generation tyrosine kinase inhibitor.
Many therapeutic approaches are aimed at EGFR. Cetuximab and panitumumab are examples of monoclonal antibody inhibitors. But the first is the type IgG1, the last of the type IgG2; the consequences on the cellular cytotoxicity of antibodies can be very different. Other monoclones in clinical development are zalutumumab, nimotuzumab, and matuzumab. Monoclonal antibodies block the extracellular ligand binding domain. With binding sites blocked, signal molecules can no longer stick there and activate tyrosine kinase.
Another method is to use small molecules to inhibit EGFR tyrosine kinase, which is on the cytoplasm side of the receptor. Without kinase activity, EGFR can not activate itself, which is a prerequisite for binding downstream adapter proteins. As if by stopping cascade signals in cells that depend on these pathways for growth, tumor proliferation and migration decreases. Gefitinib, erlotinib, brigatinib and lapatinib (a mixture of EGFR and ERBB2 inhibitors) are examples of small molecule inhibitor kinases.
CimaVax-EGF, an active vaccine targeting EGF as the main ligand of EGF, uses a different approach, improves antibodies to EGF itself, thus denying EGFR-dependent cancer from proliferative stimuli; it is used 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 licenses in Japan, Europe, and the United States.
There are several available quantitative methods that use detection of protein phosphorylation to identify EGFR family inhibitors.
New drugs such as osimertinib, gefitinib, erlotinib and brigatinib directly target EGFR. Patients have been divided into EGFR-positive and EGFR-negative, based on whether tissue tests show mutations. EGFR-positive patients have shown a 60% response rate, which exceeds the response rate for conventional chemotherapy.
However, many patients develop resistance. The two main sources of resistance are T790M Mutation and MET oncogenes. However, in 2010 there was no consensus approach accepted to combat FDA resistance or approval of certain combinations. Phase II clinical trial results reported for brigatinib targeted the T790M mutation, and brigatinib received FDA Breakthrough Therapy status indicator in February 2015.
The most common side effect of an EGFR inhibitor, found in over 90% of patients, is a papulopustular rash that spreads across the face and body; The presence of a rash correlates with the antitumor effect of the drug. In 10% to 15% of patients, the effects can be serious and require treatment.
Some tests aim to predict the benefits of EGFR treatment, such as Veristrat.
Laboratory studies using genetically engineered stem cells to target EGFR in mice were reported in 2014 to show promise. EGFR is an established target for certain monoclonal antibodies and tyrosine kinase inhibitors.
Goal for imagery agents
An imaging agent has been developed that identifies EGFR-dependent cancers using labeled EGF. The feasibility of in vivo imaging of EGFR expression has been demonstrated in several studies.
Interactions
Epidermal growth factor receptors have been shown to interact with:
In fruits, the epidermal growth factor receptor interacts with Spitz.
References
Further reading
External links
- Epidermal Growth Factor Receptor at US National Library of Medicine's Medical Subject Headings (MeSH)
Source of the article : Wikipedia
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