Apoptosis is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to death; these changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, global mRNA decay. The average adult human loses between 70 billion cells each day due to apoptosis. For an average human child between the ages of 8 to 14 year old 20 to 30 billion cells die per day. In contrast to necrosis, a form of traumatic cell death that results from acute cellular injury, apoptosis is a regulated and controlled process that confers advantages during an organism's lifecycle. For example, the separation of fingers and toes in a developing human embryo occurs because cells between the digits undergo apoptosis. Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that phagocytic cells are able to engulf and remove before the contents of the cell can spill out onto surrounding cells and cause damage to them; because apoptosis cannot stop once it has begun, it is a regulated process.
Apoptosis can be initiated through one of two pathways. In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. Weak external signals may activate the intrinsic pathway of apoptosis. Both pathways induce cell death by activating caspases, which are proteases, or enzymes that degrade proteins; the two pathways both activate initiator caspases, which activate executioner caspases, which kill the cell by degrading proteins indiscriminately. Research on apoptosis has increased since the early 1990s. In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in a wide variety of diseases. Excessive apoptosis causes atrophy, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer; some factors like Fas receptors and caspases promote apoptosis, while some members of the Bcl-2 family of proteins inhibit apoptosis.
German scientist Karl Vogt was first to describe the principle of apoptosis in 1842. In 1885, anatomist Walther Flemming delivered a more precise description of the process of programmed cell death. However, it was not until 1965. While studying tissues using electron microscopy, John Foxton Ross Kerr at the University of Queensland was able to distinguish apoptosis from traumatic cell death. Following the publication of a paper describing the phenomenon, Kerr was invited to join Alastair R. Currie, as well as Andrew Wyllie, Currie's graduate student, at University of Aberdeen. In 1972, the trio published a seminal article in the British Journal of Cancer. Kerr had used the term programmed cell necrosis, but in the article, the process of natural cell death was called apoptosis. Kerr and Currie credited James Cormack, a professor of Greek language at University of Aberdeen, with suggesting the term apoptosis. Kerr received the Paul Ehrlich and Ludwig Darmstaedter Prize on March 14, 2000, for his description of apoptosis.
He shared the prize with Boston biologist H. Robert Horvitz. For many years, neither "apoptosis" nor "programmed cell death" was a cited term. Two discoveries brought cell death from obscurity to a major field of research: identification of components of the cell death control and effector mechanisms, linkage of abnormalities in cell death to human disease, in particular cancer; the 2002 Nobel Prize in Medicine was awarded to Sydney Brenner and John E. Sulston for their work identifying genes that control apoptosis; the genes were identified by studies in the nematode C. elegans and homologues of these genes function in humans to regulate apoptosis. In Greek, apoptosis translates to the "falling off" of leaves from a tree. Cormack, professor of Greek language, reintroduced the term for medical use as it had a medical meaning for the Greeks over two thousand years before. Hippocrates used the term to mean "the falling off of the bones". Galen extended its meaning to "the dropping of the scabs".
Cormack was no doubt aware of this usage. Debate continues over the correct pronunciation, with opinion divided between a pronunciation with the second p silent and the second p pronounced, as in the original Greek. In English, the p of the Greek -pt- consonant cluster is silent at the beginning of a word, but articulated when used in combining forms preceded by a vowel, as in helicopter or the orders of insects: diptera, etc. In the original Kerr, Wyllie & Currie paper, there is a footnote regarding the pronunciation: "We are most grateful to Professor James Cormack of the Department of Greek, University of Aberdeen, for suggesting this term; the word "apoptosis" is used in Greek to describe the "dropping off" or "falling off" of petals from flowers, or leaves from trees. To show the derivation we propose that the stress should be on the penultimate syllable, the second half of the word being pronounced like "ptosis", which comes from the same root "to fall", is used to describe the drooping of the upper eyelid."
The initiation of apoptosis is regulated by activation mechanisms, because once apoptosis has begun, it leads to the death of the cell. The two best-understood activation mechanisms are the extrinsic pathway; the intrinsic pathway is activated by intracellular signals generated when cells are stressed and depends on the release of proteins from th
Carcinogenesis called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in all tissues and under a variety of circumstances; the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by disrupting the programming regulating the processes, upsetting the normal balance between proliferation and cell death; this results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer. Variants of inherited genes may predispose individuals to cancer.
In addition, environmental factors such as carcinogens and radiation cause mutations that may contribute to the development of cancer. Random mistakes in normal DNA replication may result in cancer causing mutations. A series of several mutations to certain classes of genes is required before a normal cell will transform into a cancer cell. On average, for example, 15 "driver mutations" and 60 "passenger" mutations are found in colon cancers. Mutations in genes that regulate cell division, DNA repair may result in uncontrolled cell proliferation and cancer. Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes that regulate cell growth and differentiation must be altered. Genetic and epigenetic changes can occur at many levels, from gain or loss of entire chromosomes, to a mutation affecting a single DNA nucleotide, or to silencing or activating a microRNA that controls expression of 100 to 500 genes. There are two broad categories of genes.
Oncogenes may be normal genes that are expressed at inappropriately high levels, or altered genes that have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes that inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are disabled by cancer-promoting genetic changes. Oncovirinae, viruses that contain an oncogene, are categorized as oncogenic because they trigger the growth of tumorous tissues in the host; this process is referred to as viral transformation. There is a diverse classification scheme for the various genomic changes that may contribute to the generation of cancer cells. Many of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. There are many epigenetic changes that alter whether genes are expressed or not expressed. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change, not a mutation, may involve either gain or loss of one or more chromosomes through errors in mitosis.
Large-scale mutations involve the gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies of a small chromosomal region containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase. Small-scale mutations include point mutations and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may result from integration of genomic material from a DNA virus or retrovirus, such an event may result in the expression of viral oncogenes in the affected cell and its descendants.
DNA damage is considered to be the primary cause of cancer. More than 60,000 new occurring DNA damages arise, on average, per human cell, per day, due to endogenous cellular processes. Additional DNA damages can arise from exposure to exogenous agents; as one example of an exogenous carcinogeneic agent, tobacco smoke causes increased DNA damage, these DNA damages cause the increase of lung cancer due to smoking. In other examples, UV light from solar radiation causes DNA damage, important in melanoma, helicobacter pylori infection produces high levels of reactive oxygen species that damage DNA and contributes to gastric cancer, the Aspergillus metabolite, aflatoxin, is a DNA damaging agent, causative in liver cancer. DNA damages can be caused by endogenous agents. Macrophages and neutrophils in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damages that initiate colonic tumorigenesis, bile acids, at high levels in the colons of humans eating a high fat diet cause DNA damage and contribute to colon cancer.
Such exogenous and endogenous sources of DNA damage are indicated in the boxes at the top of the figure in this section. The central role of DNA damage in progression to cancer is indicated at the second level of the figure; the central elements of DNA damage, epigenetic alterations and deficient DNA repair in progression to cancer are shown in red. A deficiency in DNA repair would cause more
Monoclonal antibodies are antibodies that are made by identical immune cells that are all clones of a unique parent cell. Monoclonal antibodies can have monovalent affinity. In contrast, polyclonal antibodies bind to multiple epitopes and are made by several different plasma cell lineages. Bispecific monoclonal antibodies can be engineered, by increasing the therapeutic targets of one single monoclonal antibody to two epitopes. Given any substance, it is possible to produce monoclonal antibodies that bind to that substance; this has become an important tool in biochemistry, molecular biology, medicine. When used as medications, non-proprietary drug names end in -mab and many immunotherapy specialists use the word mab anacronymically; the idea of "magic bullets" was first proposed by Paul Ehrlich, who, at the beginning of the 20th century, postulated that, if a compound could be made that selectively targeted a disease-causing organism a toxin for that organism could be delivered along with the agent of selectivity.
He and Élie Metchnikoff received the 1908 Nobel Prize for Physiology or Medicine for this work, which led to an effective syphilis treatment by 1910. In the 1970s, the B-cell cancer multiple myeloma was known, it was understood. This was used to study the structure of antibodies, but it was not yet possible to produce identical antibodies specific to a given antigen. In 1975, Georges Köhler and César Milstein succeeded in making fusions of myeloma cell lines with B cells to create hybridomas that could produce antibodies, specific to known antigens and that were immortalized, they shared the Nobel Prize in Medicine in 1984 for the discovery. In 1988, Greg Winter and his team pioneered the techniques to humanize monoclonal antibodies, eliminating the reactions that many monoclonal antibodies caused in some patients. Much of the work behind production of monoclonal antibodies is rooted in the production of hybridomas, which involves identifying antigen-specific plasma/plasmablast cells that produce antibodies specific to an antigen of interest and fusing these cells with myeloma cells.
Rabbit B-cells can be used to form a rabbit hybridoma. Polyethylene glycol is used to fuse adjacent plasma membranes, but the success rate is low, so a selective medium in which only fused cells can grow is used; this is possible because myeloma cells have lost the ability to synthesize hypoxanthine-guanine-phosphoribosyl transferase, an enzyme necessary for the salvage synthesis of nucleic acids. The absence of HGPRT is not a problem for these cells unless the de novo purine synthesis pathway is disrupted. Exposing cells to aminopterin, makes them unable to use the de novo pathway and become auxotrophic for nucleic acids, thus requiring supplementation to survive; the selective culture medium is called HAT medium because it contains hypoxanthine and thymidine. This medium is selective for fused cells. Unfused myeloma cells cannot grow because they lack HGPRT and thus cannot replicate their DNA. Unfused spleen cells cannot grow indefinitely because of their limited life span. Only fused hybrid cells, referred to as hybridomas, are able to grow indefinitely in the medium because the spleen cell partner supplies HGPRT and the myeloma partner has traits that make it immortal.
This mixture of cells is diluted and clones are grown from single parent cells on microtitre wells. The antibodies secreted by the different clones are assayed for their ability to bind to the antigen or immuno-dot blot; the most productive and stable clone is selected for future use. The hybridomas can be grown indefinitely in a suitable cell culture medium, they can be injected into mice. There, they produce; the medium must be enriched during in vitro selection to further favour hybridoma growth. This can be achieved by the use of a layer of feeder fibrocyte cells or supplement medium such as briclone. Culture-media conditioned by macrophages can be used. Production in cell culture is preferred as the ascites technique is painful to the animal. Where alternate techniques exist, ascites is considered unethical. Several monoclonal antibody technologies had been developed such as phage display, single B cell culture, single cell amplification from various B cell populations and single plasma cell interrogation technologies.
Different from traditional hybridoma technology, the newer technologies use molecular biology techniques to amplify the heavy and light chains of the antibody genes by PCR and produce in either bacterial or mammalian systems with recombinant technology. One of the advantages of the new technologies is applicable to multiple animals, such as rabbit, llama and other common experimental animals in the laboratory. After obtaining either a media sample of cultured hybridomas or a sample of ascites fluid, the desired antibodies must be extracted. Cell culture sample contaminants consist of media components such as growth factors and transferrins. In contrast, the in vivo sample is to have host antibodies, nucleases, nucleic acids and viruses. In both cases, other secretions by the hybridomas such as cytokines may be present. There may be b
A tyrosine kinase inhibitor is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades; the proteins are activated by adding a phosphate group to a step that TKIs inhibit. TKIs are used as anticancer drugs. For example, they have improved outcomes in chronic myelogenous leukemia, they are called tyrphostins, the short name for “tyrosine phosphorylation inhibitor” coined in a 1988 publication, the first description of compounds inhibiting the catalytic activity of the epidermal growth factor receptor. The 1988 study was the first demonstration of a systematic search and discovery of small-molecular-weight inhibitors of tyrosine phosphorylation, which do not inhibit protein kinases that phosphorylate serine or threonine residues and can discriminate between the kinase domains of the EGFR and that of the insulin receptor, it was further shown that in spite of the conservation of the tyrosine-kinase domains one can design and synthesize tyrphostins that discriminate between closely related protein tyrosine kinases such as EGFR and its close relative HER2.
Numerous TKIs aiming at various tyrosine kinases have been generated by the originators of these compounds and proven to be effective anti-tumor agents and anti-leukemic agents. Based on this work imatinib was developed against chronic myelogenous leukemia and gefitinib and erlotinib aiming at the EGF receptor. Sunitinib, an inhibitor of the receptors for FGF, PDGF and VEGF is based on early studies on TKIs aiming at VEGF receptors. Adavosertib referred to as AZD1775 or MK17750, is a Wee1 kinase inhibitor, undergoing numerous clinical trials in the treatment of refractory solid tumors. However, toxicities such as myelosuppression and supraventricular tachyarrhythmia have arisen while attempting to determine the toxicity and effectiveness of the drug. Lapatinib, FDA approved for treatment in conjunction with chemotherapy or hormone therapy, is currently undergoing clinical trials in the treatment of HER2-overexpressing breast cancers as it is suggested intermittent high-dose therapy might have better efficacy with manageable toxicity than the standard continuous dosing.
A Phase I clinical trial found responses and dramatic responses to this line of treatment, with the most common toxicity being diarrhea. TKIs operate by four different mechanisms: they can compete with adenosine triphosphate, the phosphorylating entity, the substrate or both or can act in an allosteric fashion, namely bind to a site outside the active site, affecting its activity by a conformational change. TKIs have been shown to deprive tyrosine kinases of access to the Cdc37-Hsp90 molecular chaperone system on which they depend for their cellular stability, leading to their ubiquitylation and degradation. Signal transduction therapy can in principle apply for non-cancer proliferative diseases and for inflammatory conditions; until now TKIs have not been developed for the treatment of such conditions. Bcr-Abl tyrosine-kinase inhibitor Protein kinase inhibitor
A biopharmaceutical known as a biologic medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from synthesized pharmaceuticals, they include vaccines, blood components, somatic cells, gene therapies, recombinant therapeutic protein, living cells used in cell therapy. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living cells or tissues, they are isolated from living sources—human, plant, fungal, or microbial. Terminology surrounding biopharmaceuticals varies between groups and entities, with different terms referring to different subsets of therapeutics within the general biopharmaceutical category; some regulatory agencies use the terms biological medicinal products or therapeutic biological product to refer to engineered macromolecular products like protein- and nucleic acid-based drugs, distinguishing them from products like blood, blood components, or vaccines, which are extracted directly from a biological source.
Specialty drugs, a recent classification of pharmaceuticals, are high-cost drugs that are biologics. The European Medicines Agency uses the term advanced therapy medicinal products for medicines for human use that are "based on genes, cells, or tissue engineering", including gene therapy medicines, somatic-cell therapy medicines, tissue-engineered medicines, combinations thereof. Within EMA contexts, the term advanced therapies refers to ATMPs, although that term is rather nonspecific outside those contexts. Gene-based and cellular biologics, for example are at the forefront of biomedical research, may be used to treat a variety of medical conditions for which no other treatments are available. In some jurisdictions, biologics are regulated via different pathways than other small molecule drugs and medical devices; the term biopharmacology is sometimes used to describe the branch of pharmacology that studies biopharmaceuticals. Some of the oldest forms of biologics are extracted from the bodies of animals, other humans especially.
Important biologics include: Whole blood and other blood components Organs and tissue transplants Stem cell therapy Antibodies for passive immunization Human breast milk Fecal microbiota Human reproductive cellsSome biologics that were extracted from animals, such as insulin, are now more produced by recombinant DNA. As indicated the term "biologics" can be used to refer to a wide range of biological products in medicine. However, in most cases, the term "biologics" is used more restrictively for a class of therapeutics that are produced by means of biological processes involving recombinant DNA technology; these medications are one of three types: Substances that are identical to the body's own key signalling proteins. Examples are the blood-production stimulating protein erythropoetin, or the growth-stimulating hormone named "growth hormone" or biosynthetic human insulin and its analogues. Monoclonal antibodies; these are similar to the antibodies that the human immune system uses to fight off bacteria and viruses, but they are "custom-designed" and can therefore be made to counteract or block any given substance in the body, or to target any specific cell type.
Receptor constructs based on a occurring receptor linked to the immunoglobulin frame. In this case, the receptor provides the construct with detailed specificity, whereas the immunoglobulin-structure imparts stability and other useful features in terms of pharmacology; some examples are listed in the table below. Biologics as a class of medications in this narrower sense have had a profound impact on many medical fields rheumatology and oncology, but cardiology, gastroenterology and others. In most of these disciplines, biologics have added major therapeutic options for the treatment of many diseases, including some for which no effective therapies were available, others where existing therapies were inadequate. However, the advent of biologic therapeutics has raised complex regulatory issues, significant pharmacoeconomic concerns, because the cost for biologic therapies has been higher than for conventional medications; this factor has been relevant since many biological medications are used for the treatment of chronic diseases, such as rheumatoid arthritis or inflammatory bowel disease, or for the treatment of otherwise untreatable cancer during the remainder of life.
The cost of treatment with a typical monoclonal antibody therapy for common indications is in the range of €7,000–14,000 per patient per year. Older patients who receive biologic therapy for diseases such as rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis are at increased risk for life-threatening infection, adverse cardiovascular events, malignancy; the first such substance approved for therapeutic use was biosynthetic "human" insulin made via recombinant DNA. Sometimes referred to as rHI, under the trade name Humulin, was developed by Genentech, but licensed to Eli Lilly and Company, who manufactured and marketed it starting in 1982. Major kinds of biopharmaceuticals include: Blood factors Thrombolytic agents Hormones (insulin, growth hormone, gonadotr
A molecule is an electrically neutral group of two or more atoms held together by chemical bonds. Molecules are distinguished from ions by their lack of electrical charge. However, in quantum physics, organic chemistry, biochemistry, the term molecule is used less also being applied to polyatomic ions. In the kinetic theory of gases, the term molecule is used for any gaseous particle regardless of its composition. According to this definition, noble gas atoms are considered molecules as they are monatomic molecules. A molecule may be homonuclear, that is, it consists of atoms of one chemical element, as with oxygen. Atoms and complexes connected by non-covalent interactions, such as hydrogen bonds or ionic bonds, are not considered single molecules. Molecules as components of matter are common in organic substances, they make up most of the oceans and atmosphere. However, the majority of familiar solid substances on Earth, including most of the minerals that make up the crust and core of the Earth, contain many chemical bonds, but are not made of identifiable molecules.
No typical molecule can be defined for ionic crystals and covalent crystals, although these are composed of repeating unit cells that extend either in a plane or three-dimensionally. The theme of repeated unit-cellular-structure holds for most condensed phases with metallic bonding, which means that solid metals are not made of molecules. In glasses, atoms may be held together by chemical bonds with no presence of any definable molecule, nor any of the regularity of repeating units that characterizes crystals; the science of molecules is called molecular chemistry or molecular physics, depending on whether the focus is on chemistry or physics. Molecular chemistry deals with the laws governing the interaction between molecules that results in the formation and breakage of chemical bonds, while molecular physics deals with the laws governing their structure and properties. In practice, this distinction is vague. In molecular sciences, a molecule consists of a stable system composed of two or more atoms.
Polyatomic ions may sometimes be usefully thought of as electrically charged molecules. The term unstable molecule is used for reactive species, i.e. short-lived assemblies of electrons and nuclei, such as radicals, molecular ions, Rydberg molecules, transition states, van der Waals complexes, or systems of colliding atoms as in Bose–Einstein condensate. According to Merriam-Webster and the Online Etymology Dictionary, the word "molecule" derives from the Latin "moles" or small unit of mass. Molecule – "extremely minute particle", from French molécule, from New Latin molecula, diminutive of Latin moles "mass, barrier". A vague meaning at first; the definition of the molecule has evolved. Earlier definitions were less precise, defining molecules as the smallest particles of pure chemical substances that still retain their composition and chemical properties; this definition breaks down since many substances in ordinary experience, such as rocks and metals, are composed of large crystalline networks of chemically bonded atoms or ions, but are not made of discrete molecules.
Molecules are held together by ionic bonding. Several types of non-metal elements exist only as molecules in the environment. For example, hydrogen only exists as hydrogen molecule. A molecule of a compound is made out of two or more elements. A covalent bond is a chemical bond; these electron pairs are termed shared pairs or bonding pairs, the stable balance of attractive and repulsive forces between atoms, when they share electrons, is termed covalent bonding. Ionic bonding is a type of chemical bond that involves the electrostatic attraction between oppositely charged ions, is the primary interaction occurring in ionic compounds; the ions are atoms that have lost one or more electrons and atoms that have gained one or more electrons. This transfer of electrons is termed electrovalence in contrast to covalence. In the simplest case, the cation is a metal atom and the anion is a nonmetal atom, but these ions can be of a more complicated nature, e.g. molecular ions like NH4+ or SO42−. An ionic bond is the transfer of electrons from a metal to a non-metal for both atoms to obtain a full valence shell.
Most molecules are far too small to be seen with the naked eye. DNA, a macromolecule, can reach macroscopic sizes, as can molecules of many polymers. Molecules used as building blocks for organic synthesis have a dimension of a few angstroms to several dozen Å, or around one billionth of a meter. Single molecules cannot be observed by light, but small molecules and the outlines of individual atoms may be traced in some circumstances by use of an atomic force microscope; some of the largest molecules are supermolecules. The smallest molecule is the diatomic hydrogen, with a bond length of 0.74 Å. Effective molecular radius is the size; the table of permselectivity for different substances contains examples. The chemical formula for a molecule uses one line of chemical element symbols and sometimes al
Epidermal growth factor receptor
The epidermal growth factor receptor is a transmembrane protein, a receptor for members of the epidermal growth factor family of extracellular protein ligands. The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four related receptor tyrosine kinases: EGFR, HER2/neu, Her 3 and Her 4. In many cancer types, mutations affecting EGFR expression or activity could result in cancer. 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 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 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 is a transmembrane protein, activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor α ErbB2 has no known direct activating ligand, 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 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 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 residues in the C-terminal domain of EGFR occurs. These include 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 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 and proliferation. Activation of the receptor is important for the innate immune response in human skin; the kinase domain of EGFR can cross-phosphorylate tyrosine residues of other receptors it is aggregated with, can itself be activated in that manner. The EGFR is essential for ductal development of the mammary glands, agonists of the EGFR such as amphiregulin, TGF-α, heregulin induce both ductal and lobuloalveolar development in the absence of estrogen and progesterone.
Mutations that lead to EGFR overexpression have been associated with a number of cancers, including adenocarcinoma of the lung, anal cancers and epithelian tumors of the head and neck. 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 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 and atherosclerosis. However, its exact roles in these conditions are ill-defined. 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.
EGFR has been shown to play 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; the identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including gefitinib, afatinib and icotinib for lung cancer, cetuximab for colon cancer. More 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 inhibitors; however the former is of the latter of the IgG2 type. Other monoclonals in clinical development are zalutumumab and matuzumab; the monoclonal antibodies block. 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, whi