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56-559: 1956,https://ncbi.nlm.nih.gov/gene?cmd=retrieve&dopt=default&rn=1&list_uids=1956 1956,https://ncbi.nlm.nih.gov/gene?cmd=retrieve&dopt=default&rn=1&list_uids=1956 13649 ENSG00000146648 ENSMUSG00000020122 P00533 Q01279 NM_005228 NM_201282 NM_201283 NM_201284 NM_007912 NM_207655 NP_005219 NP_958439 NP_958440 NP_958441 NP_031938 NP_997538 The epidermal growth factor receptor ( EGFR ; ErbB-1 ; HER1 in humans)

112-734: A critical role in TGF-beta1 dependent fibroblast 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 ). 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 , brigatinib and icotinib for lung cancer, and cetuximab for colon cancer . More recently AstraZeneca has developed Osimertinib ,

168-623: A needle biopsy of a primary breast cancer, a new HER2 test may be performed on the subsequent breast excision. The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation. Measurement of serum HER2 by enzyme-linked immunosorbent assay ( ELISA ) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated. Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to trastuzumab therapy. However, its ability to determine eligibility for trastuzumab therapy

224-631: 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

280-499: A signal-anchor sequence, with type II being targeted to the ER lumen with its C-terminal domain, while type III have their N-terminal domains targeted to the ER lumen. Type IV is subdivided into IV-A, with their N-terminal domains targeted to the cytosol and IV-B, with an N-terminal domain targeted to the lumen. The implications for the division in the four types are especially manifest at the time of translocation and ER-bound translation, when

336-549: 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. In 10% to 15% of patients

392-407: 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. Aberrant EGFR signaling has been implicated in psoriasis, eczema and atherosclerosis. However, its exact roles in these conditions are ill-defined. A single child displaying multi-organ epithelial inflammation

448-611: A third generation tyrosine kinase inhibitor. 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 . The monoclonal antibodies block

504-534: 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

560-410: A transmembrane domain, and an intracellular domain that can interact with a multitude of signaling molecules and exhibit both ligand-dependent and ligand-independent activity. Notably, no ligands for HER2 have yet been identified. HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors. Dimerisation results in

616-403: A valine for a glutamic acid or a glutamine in the transmembrane domain can result in the constitutive dimerisation of this protein in the absence of a ligand. HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment. HER2 is the target of the monoclonal antibody trastuzumab (marketed as Herceptin). Trastuzumab is effective only in cancers where HER2

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672-531: Is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene . ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 (human epidermal growth factor receptor 2) or CD340 ( cluster of differentiation 340). HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family . But contrary to other members of

728-567: Is a transmembrane protein that is a receptor for members of the epidermal growth factor 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 . Epidermal growth factor and its receptor

784-469: Is a peptide-based immunotherapy that directs "killer" T cells to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials. It has been found that patients with ER+ ( Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway. Over-expression of HER2 can also be suppressed by

840-564: Is an increase in p27 , a protein that halts cell proliferation. Another monoclonal antibody, Pertuzumab , which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012. As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. margetuximab . Additionally, NeuVax ( Galena Biopharma )

896-606: Is colocalised and most of the time, coamplified with the gene GRB7 , which is a proto-oncogene associated with breast, testicular germ cell, gastric, and esophageal tumours. HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis. Evidence has also implicated HER2 signaling in resistance to the EGFR -targeted cancer drug cetuximab . The high expression of HER2 correlates with better survival in esophageal adenocarcinoma. The high amplification of HER2 copy number positively contributes to

952-482: Is generally used to measure the amount of HER2 protein present in the sample, with fluorescence in situ hybridisation (FISH) being used on samples that are equivocal in IHC. However, in several locations, FISH is used initially, followed by IHC in equivocal cases. By immunohistochemistry, the sample is given a score based on the cell membrane staining pattern. Micrographs showing each score: FISH can be used to measure

1008-558: 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

1064-430: Is important that trastuzumab is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity. For HER2-positive tumors, the benefits of trastuzumab clearly outweigh the risks. Tests are usually performed on breast biopsy samples obtained by either fine-needle aspiration , core needle biopsy, vacuum-assisted breast biopsy , or surgical excision. Immunohistochemistry (IHC)

1120-464: Is over-expressed. One year of trastuzumab therapy is recommended for all patients with HER2-positive breast cancer who are also receiving chemotherapy. Twelve months of trastuzumab therapy is optimal. Randomized trials have demonstrated no additional benefit beyond 12 months, whereas 6 months has been shown to be inferior to 12. Trastuzumab is administered intravenously weekly or every 3 weeks. An important downstream effect of trastuzumab binding to HER2

1176-429: Is technically difficult. There are relatively few examples of the successful refolding experiments, as for bacteriorhodopsin . In vivo , all such proteins are normally folded co-translationally within the large transmembrane translocon . The translocon channel provides a highly heterogeneous environment for the nascent transmembrane α-helices. A relatively polar amphiphilic α-helix can adopt a transmembrane orientation in

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1232-400: Is thought that β-barrel membrane proteins come from one ancestor even having different number of sheets which could be added or doubled during evolution. Some studies show a huge sequence conservation among different organisms and also conserved amino acids which hold the structure and help with folding. Note: n and S are, respectively, the number of beta-strands and the "shear number" of

1288-426: The autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways. Signaling pathways activated by HER2 include: In summary, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis , and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring. Amplification, also known as

1344-912: The beta-barrel Her2 1MFG , 1MFL , 1MW4 , 1N8Z , 1QR1 , 1S78 , 2A91 , 2JWA , 2KS1 , 2L4K , 3BE1 , 3H3B , 3N85 , 3PP0 , 3RCD , 3MZW , 3WLW , 3WSQ , 4GFU , 4HRL , 4HRM , 4HRN , 2N2A 2064 13866 ENSG00000141736 ENSMUSG00000062312 P04626 P70424 NM_001005862 NM_001289936 NM_001289937 NM_001289938 NM_004448 NM_001003817 NM_010152 NP_001369711 NP_001369712 NP_001369713 NP_001369714 NP_001369715 NP_001369716 NP_001369717 NP_001369718 NP_001369719 NP_001369720 NP_001369721 NP_001369722 NP_001369723 NP_001369724 NP_001369725 NP_001369726 NP_001369727 NP_001369728 NP_001369729 NP_001369730 NP_001369731 NP_001369732 NP_001369733 NP_001369734 NP_001369735 NP_001003817 Receptor tyrosine-protein kinase erbB-2

1400-521: The detergent . For example, the "unfolded" bacteriorhodopsin in SDS micelles has four transmembrane α-helices folded, while the rest of the protein is situated at the micelle-water interface and can adopt different types of non-native amphiphilic structures. Free energy differences between such detergent-denatured and native states are similar to stabilities of water-soluble proteins (< 10 kcal/mol). Refolding of α-helical transmembrane proteins in vitro

1456-468: The molten globule states, formation of non-native disulfide bonds , or unfolding of peripheral regions and nonregular loops that are locally less stable. It is also important to properly define the unfolded state . The unfolded state of membrane proteins in detergent micelles is different from that in the thermal denaturation experiments. This state represents a combination of folded hydrophobic α-helices and partially unfolded segments covered by

1512-540: The oncogene later found to code for EGFR . Molecular cloning of the gene showed that HER2, Neu, and ErbB-2 are all encoded by the same orthologs . ERBB2 , a known proto-oncogene , is located at the long arm of human chromosome 17 (17q12). The ErbB family consists of four individual plasma membrane -bound receptor tyrosine kinases . One of which is erbB-2, and the other members being erbB-1 , erbB-3 (neuregulin-binding; lacks kinase domain), and erbB-4 . All four contain an extracellular ligand binding domain,

1568-513: The position of the protein N- and C-termini on the different sides of the lipid bilayer . Types I, II, III and IV are single-pass molecules . Type I transmembrane proteins are anchored to the lipid membrane with a stop-transfer anchor sequence and have their N-terminal domains targeted to the endoplasmic reticulum (ER) lumen during synthesis (and the extracellular space, if mature forms are located on cell membranes ). Type II and III are anchored with

1624-478: 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

1680-452: The ERBB family, HER2 does not directly bind ligand. HER2 activation results from heterodimerization with another ERBB member or by homodimerization when HER2 concentration are high, for instance in cancer. Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer . In recent years

1736-462: The absence of estrogen and progesterone . Mutations that lead to EGFR overexpression (known as upregulation or amplification) have been associated with a number of cancers , 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

Epidermal growth factor receptor - Misplaced Pages Continue

1792-415: The amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect. The expression of HER2 is regulated by signaling through estrogen receptors. Normally, estradiol and tamoxifen acting through the estrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2 ,

1848-752: The effects can be serious and require treatment. Some tests are aiming at predicting benefit from EGFR treatment, as Veristrat . 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. 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

1904-477: The expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer . Among approved anti-HER2 therapeutics are also tyrosine kinase inhibitors ( Lapatinib , Neratinib , and Tucatinib ) and antibody-drug conjugates ( ado-trastuzumab emtansine and trastuzumab deruxtecan ). HER2 testing is performed on breast biopsy of breast cancer patients to assess prognosis and to determine suitability for trastuzumab therapy. It

1960-636: 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. Epidermal growth factor receptor (EGFR) is a transmembrane protein that is activated by binding of its specific ligands , including epidermal growth factor and transforming growth factor alpha (TGF-α). 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

2016-428: 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

2072-415: The innate immune response in human skin. Additionally, the kinase domain of the EGFR can cross-phosphorylate the tyrosine residues of other receptors with which it is aggregated and thereby activate itself. The EGFR is essential for ductal development of the mammary glands , and agonists of the EGFR such as amphiregulin , TGF-α , and heregulin induce both ductal and lobuloalveolar development even in

2128-859: The membrane, but do not pass through it. There are two basic types of transmembrane proteins: alpha-helical and beta barrels . Alpha-helical proteins are present in the inner membranes of bacterial cells or the plasma membrane of eukaryotic cells, and sometimes in the bacterial outer membrane . This is the major category of transmembrane proteins. In humans, 27% of all proteins have been estimated to be alpha-helical membrane proteins. Beta-barrel proteins are so far found only in outer membranes of gram-negative bacteria , cell walls of gram-positive bacteria , outer membranes of mitochondria and chloroplasts , or can be secreted as pore-forming toxins . All beta-barrel transmembrane proteins have simplest up-and-down topology, which may reflect their common evolutionary origin and similar folding mechanism. In addition to

2184-399: The membrane, or the transmembrane segment , is largely hydrophobic and can be visualized using the hydropathy plot . Depending on the number of transmembrane segments, transmembrane proteins can be classified as single-pass membrane proteins , or as multipass membrane proteins. Some other integral membrane proteins are called monotopic , meaning that they are also permanently attached to

2240-461: The number of copies of the gene which are present and is thought to be more reliable than immunohistochemistry. It usually uses chromosome enumeration probe 17 (CEP17) to count the amount of chromosomes. Hence, the HER2/CEP17 ratio reflects any amplification of HER2 as compared to the number of chromosomes. The signals of 20 cells are usually counted. If the initial HER2 result is negative for

2296-434: The otherwise poor prognosis of the historically problematic difficulties associated with HER2-positive breast cancer. Over-expression is also known to occur in ovarian, stomach, adenocarcinoma of the lung and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma , e.g. HER2 is over-expressed in approximately 7-34% of patients with gastric cancer and in 30% of salivary duct carcinomas. HER2

Epidermal growth factor receptor - Misplaced Pages Continue

2352-546: The over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers . HER2-positive breast cancers are well established as being associated with increased disease recurrence and a poor prognosis compared with other identifiably genetically distinct breast cancers with other known, or lack thereof, genetic markers that are thought to be associated with other breast cancers; however, drug agents targeting HER2 in breast cancer have significantly and positively altered

2408-459: 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

2464-462: The positive inside rule and other methods have been developed. Transmembrane alpha-helical (α-helical) proteins are unusually stable judging from thermal denaturation studies, because they do not unfold completely within the membranes (the complete unfolding would require breaking down too many α-helical H-bonds in the nonpolar media). On the other hand, these proteins easily misfold , due to non-native aggregation in membranes, transition to

2520-433: The presence of EGFR mutation in patients with non-small cell lung cancer. Epidermal growth factor receptor has been shown to interact with: In fruitflies, the epidermal growth factor receptor interacts with Spitz . Transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane . Many transmembrane proteins function as gateways to permit

2576-463: The protein domains, there are unusual transmembrane elements formed by peptides. A typical example is gramicidin A , a peptide that forms a dimeric transmembrane β-helix. This peptide is secreted by gram-positive bacteria as an antibiotic . A transmembrane polyproline-II helix has not been reported in natural proteins. Nonetheless, this structure was experimentally observed in specifically designed artificial peptides. This classification refers to

2632-421: The protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients. HER2 is so named because it has a similar structure to human epidermal growth factor receptor, or HER1 . Neu is so named because it was derived from a rodent glioblastoma cell line, a type of neural tumor. ErbB-2 was named for its similarity to ErbB (avian erythroblastosis oncogene B),

2688-690: The protein has to be passed through the ER membrane in a direction dependent on the type. Membrane protein structures can be determined by X-ray crystallography , electron microscopy or NMR spectroscopy . The most common tertiary structures of these proteins are transmembrane helix bundle and beta barrel . The portion of the membrane proteins that are attached to the lipid bilayer (see annular lipid shell ) consist mostly of hydrophobic amino acids. Membrane proteins which have hydrophobic surfaces, are relatively flexible and are expressed at relatively low levels. This creates difficulties in obtaining enough protein and then growing crystals. Hence, despite

2744-449: 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

2800-432: The significant functional importance of membrane proteins, determining atomic resolution structures for these proteins is more difficult than globular proteins. As of January 2013 less than 0.1% of protein structures determined were membrane proteins despite being 20–30% of the total proteome. Due to this difficulty and the importance of this class of proteins methods of protein structure prediction based on hydropathy plots,

2856-399: The survival time of gastric cardia adenocarcinoma patients. Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. HER2 is found in a variety of tumours and some of these tumours carry point mutations in the sequence specifying the transmembrane domain of HER2. Substitution of

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2912-443: The translocon (although it would be at the membrane surface or unfolded in vitro ), because its polar residues can face the central water-filled channel of the translocon. Such mechanism is necessary for incorporation of polar α-helices into structures of transmembrane proteins. The amphiphilic helices remain attached to the translocon until the protein is completely synthesized and folded. If the protein remains unfolded and attached to

2968-464: The translocon for too long, it is degraded by specific "quality control" cellular systems. Stability of beta barrel (β-barrel) transmembrane proteins is similar to stability of water-soluble proteins, based on chemical denaturation studies. Some of them are very stable even in chaotropic agents and high temperature. Their folding in vivo is facilitated by water-soluble chaperones , such as protein Skp. It

3024-426: The transport of specific substances across the membrane. They frequently undergo significant conformational changes to move a substance through the membrane. They are usually highly hydrophobic and aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them ( beta-barrels ) can be also extracted using denaturing agents . The peptide sequence that spans

3080-531: 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 . 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

3136-471: 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. EGFR has been shown to play

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