1GQ5
56-451: 5156 18595 ENSG00000134853 ENSMUSG00000029231 P16234 P26618 NM_006206 NM_001347827 NM_001347828 NM_001347829 NM_001347830 NM_001083316 NM_011058 NM_001347718 NM_001347719 NP_001334756 NP_001334757 NP_001334758 NP_001334759 NP_006197 NP_001076785 NP_001334647 NP_001334648 NP_035188 Platelet-derived growth factor receptor A , also termed CD140a ,
112-457: A hematological malignancy in the clonal hypereosinophilia class of malignancies. These mutations create fused genes which encode chimeric proteins that possess continuously active PDGFRA-derived tyrosine kinase . They thereby continuously stimulate cell growth and proliferation and lead to the development of leukemias , lymphomas , and myelodysplastic syndromes that are commonly associated with hypereosinophilia and therefore regarded as
168-424: A FIP1L1-PDGFRA protein that causes: a) chronic eosinophilia which progresses to chronic eosinophilic leukemia ; b) a form of myeloproliferative neoplasm / myeloblastic leukemia associated with little or no eosinophilia; c) T-lymphoblastic leukemia/lymphoma associated with eosinophilia; d) myeloid sarcoma with eosinophilia (see FIP1L1-PDGFRA fusion genes ); or e) mixtures of these presentations. Variations in
224-422: A T-lymphoblastic leukemia/lymphoma; or myeloid sarcoma; b) are diagnosed cytogenetically, usually by analyses that detect breakpoints in the short arm of chromosome 4 using Fluorescence in situ hybridization ; and c) where treated (many of the translocations are extremely rare and have not be fully tested for drug sensitivity), respond well or are anticipated to respond well to imatinib therapy as described for
280-402: A bound ligand is said to display "constitutive activity". The constitutive activity of a receptor may be blocked by an inverse agonist . The anti-obesity drugs rimonabant and taranabant are inverse agonists at the cannabinoid CB1 receptor and though they produced significant weight loss, both were withdrawn owing to a high incidence of depression and anxiety, which are believed to relate to
336-495: A constitutively (i.e. continuously) activated PDGFRα mutant receptor eventually develop fibrosis in the skin and multiple internal organs. The studies suggest that PDGFRA plays fundamental roles in the development and function of mesodermal tissues, e.g., blood cells, connective tissue, and mesangial cells. Somatic mutations that cause the fusion of the PDGFRA gene with certain other genes occur in hematopoietic stem cells and cause
392-506: A lack of mesangial cells but also suffer an ill-defined blood defect characterized by thrombocytopenic , a bleeding tendency, and severe anemia which could be due to blood loss. The mice die at or shortly before birth. PDGF-A and PDGF-C seem to be the important activators of PDGFRα during development because mice lacking functional genes for both these PDGFRA activating ligands, i.e. Pdgfa / Pdgfc- double null mice show similar defects to Pdgra null mice. Mice genetically engineered to express
448-435: A ligand binds to a corresponding receptor, it activates or inhibits the receptor's associated biochemical pathway, which may also be highly specialised. Receptor proteins can be also classified by the property of the ligands. Such classifications include chemoreceptors , mechanoreceptors , gravitropic receptors , photoreceptors , magnetoreceptors and gasoreceptors. The structures of receptors are very diverse and include
504-420: A receptor is called a ligand and can be a protein, peptide (short protein), or another small molecule , such as a neurotransmitter , hormone , pharmaceutical drug, toxin, calcium ion or parts of the outside of a virus or microbe. An endogenously produced substance that binds to a particular receptor is referred to as its endogenous ligand. E.g. the endogenous ligand for the nicotinic acetylcholine receptor
560-410: A receptor is its binding affinity, which is inversely related to the dissociation constant K d . A good fit corresponds with high affinity and low K d . The final biological response (e.g. second messenger cascade , muscle-contraction), is only achieved after a significant number of receptors are activated. Affinity is a measure of the tendency of a ligand to bind to its receptor. Efficacy
616-527: A sub-type of clonal eosinophilia. In the most common of these mutations, the PDGFRA gene on human chromosome 4 at position q12 (notated as 4q12) fuses with the FIP1L1 gene also located at position 4q12. This interstitial (i.e. on the same chromosome) fusion creates a FIP1L1 - PDGFRA fusion gene while usually losing intervening genetic material, typically including either the CHIC2 or LNX gene. The fused gene encodes
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#1733085380471672-552: A target of PDGF-B and can be selected for by the signal to then develop into mesangial cells. Mesangial cells form a glomerular functional unit with glomerular endothelial cells and podocytes through interactions of molecular signalling pathways which are essential for the formation of the glomerular tuft. Mesangial cells aid filtration by constituting part of the glomerular capillary tuft structure that filters fluids to produce urine. Communication between mesangial cells and vascular smooth muscle cells via gap junctions helps regulate
728-422: Is acetylcholine , but it can also be activated by nicotine and blocked by curare . Receptors of a particular type are linked to specific cellular biochemical pathways that correspond to the signal. While numerous receptors are found in most cells, each receptor will only bind with ligands of a particular structure. This has been analogously compared to how locks will only accept specifically shaped keys . When
784-632: Is a receptor located on the surface of a wide range of cell types. The protein is encoded in the human by the PDGFRA gene . This receptor binds to certain isoforms of platelet-derived growth factors (PDGFs) and thereby becomes active in stimulating cell signaling pathways that elicit responses such as cellular growth and differentiation . The receptor is critical for the embryonic development of certain tissues and organs, and for their maintenance, particularly hematologic tissues, throughout life. Mutations in PDGFRA , are associated with an array of clinically significant neoplasms , notably ones of
840-529: Is a deletion of codons 842 to 845. Exon 12 is the second most commonly mutated PDGFRA exon in GIST, being found in ~1% of GIST tumors. Mutations in PDGFRA's exon 14 are found in <1% of GIST tumors. While some PDGFRA mutation-induced GIST tumors are sensitive to the tyrosine kinase inhibitor, imatinib , the most common mutation, D842V, as well as some very rare mutations are resistant to this drug: median overall survival
896-464: Is a locally acting feedback mechanism. The ligands for receptors are as diverse as their receptors. GPCRs (7TMs) are a particularly vast family, with at least 810 members. There are also LGICs for at least a dozen endogenous ligands, and many more receptors possible through different subunit compositions. Some common examples of ligands and receptors include: Some example ionotropic (LGIC) and metabotropic (specifically, GPCRs) receptors are shown in
952-426: Is evidence suggesting that they originate elsewhere outside of the glomerulus and then migrate into the glomerulus during development. Human foetal and infant kidneys stained for alpha smooth muscle actin (α-SMA), a marker for mesangial cells, demonstrated that α-SMA-positive mesenchymal cells migrate towards the glomerulus and during a later stage they can be found within the mesangium. It is possible that they share
1008-444: Is mediated by paracrine factors, hormones and cAMP . In response to capillary stretching, mesangial cells can respond by producing several growth factors: TGF -1, VEGF and connective tissue growth factor . The mesangium is exposed to macromolecules from the capillary lumen as they are separated only by fenestrated endothelium without basement membrane. Mesangial cells play a role in restricting macromolecules from accumulating in
1064-413: Is not responding sufficiently to the hormone. The main receptors in the immune system are pattern recognition receptors (PRRs), toll-like receptors (TLRs), killer activated and killer inhibitor receptors (KARs and KIRs), complement receptors , Fc receptors , B cell receptors and T cell receptors . Mesangial cell Mesangial cells are specialised cells in the kidney that make up
1120-440: Is one characteristic of diabetic nephropathy although it also involves other cells in interaction including podocytes and endothelial cells. Mesangial expansion occurs due to increased deposition of extracellular matrix proteins, for example fibronectin, into the mesangium. Accumulation of extracellular matrix proteins then occurs due to insufficient degradation by matrix metalloproteinases . Increased glucose levels results in
1176-449: Is reported to be only 12.8 months in patients whose tumors bear the D842V mutation compared to 48–60 months in large series of imatinib-treated patients with other types of GIST mutations. Consequently, it is critical to define the exact nature of PDGFR -induced mutant GIST tumors in order to select appropriate therapy particularly because a novel PDGFRA selective kinase inhibitor, crenolanib ,
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#17330853804711232-411: Is the measure of the bound ligand to activate its receptor. Not every ligand that binds to a receptor also activates that receptor. The following classes of ligands exist: Note that the idea of receptor agonism and antagonism only refers to the interaction between receptors and ligands and not to their biological effects. A receptor which is capable of producing a biological response in the absence of
1288-404: Is under investigation for treating D842V-induced and other imatinib-resistant GIST tumors. A randomized trial testing the efficacy of crenolanib in patients with GIST tumors bearing the D842V mutation is under recruitment. Olaratumab (LY3012207) is a human IgG1 monoclonal antibody designed to bind to human PDGFRα with high affinity and block PDGF-AA, PDGF-BB, and PDGF-CC ligands from binding to
1344-559: The Fip1l1-PDGFRA mutation, along with the chromosomal location of PDGFRA' s partner and the notation used to identify the fused gene are given in the following table. Patients afflicted with any one of these translocation mutations, similar to those afflicted with the interstitial PDGFRA-FIP1l1 fusion gene: a) present with findings of chronic eosinophilia, hypereosinophilia, the hypereosinophilic syndrome, or chronic eosinophilic leukemia; myeloproliferative neoplasm/myeloblastic leukemia;
1400-999: The PDGFRA gene in cases of pediatric diffuse Gliomas of the pons . It appears that the initial histone H3 mutations alone are insufficient but rather require cooperating secondary mutations such as PDGFRA -activating mutations or PDGFRA amplifications to develop this type of brain tumor. In a small non-randomized trial study, imatinib therapy in patients with glioblastoma selected on the basis of having imatinib-inhibitable tyrosine kinases in biopsy tissue caused marginal disease improvement compared to similar treatment of patients with unselected recurrent glioblastoma. This suggests that patient sub-populations with excessive PDGFRA-related or other tyrosine kinase-related over-activity might benefit from imatinib therapy. Several phase I and Phase II clinical glioma/glioblastoma studies have been conducted using imatinib but no decisive follow-up phase III studies have been reported. PDGFRA has been shown to interact with: This article incorporates text from
1456-510: The United States National Library of Medicine , which is in the public domain . Receptor (biochemistry) In biochemistry and pharmacology , receptors are chemical structures, composed of protein , that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a receptor and produce physiological responses such as change in
1512-502: The afferent and efferent arterioles towards the vascular pole of the glomerulus. The extraglomerular mesangial cells are adjacent to the intraglomerular mesangial cells that are located inside the glomerulus and in between the capillaries . The primary function of mesangial cells is to remove trapped residues and aggregated protein from the basement membrane thus keeping the filter free of debris. The contractile properties of mesangial cells have been shown to be insignificant in changing
1568-460: The clonal hypereosinophilia class of malignancies, as well as gastrointestinal stromal tumors (GISTs). This gene encodes a typical receptor tyrosine kinase, which is a transmembrane protein consisting of an extracellular ligand binding domain, a transmembrane domain and an intracellular tyrosine kinase domain. The molecular mass of the mature, glycosylated PDGFRα protein is approximately 170 kDA. cell surface tyrosine kinase receptor for members of
1624-404: The electrical activity of a cell . For example, GABA , an inhibitory neurotransmitter , inhibits electrical activity of neurons by binding to GABA A receptors . There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand , and integration allows
1680-455: The mesangium of the glomerulus . Together with the mesangial matrix, they form the vascular pole of the renal corpuscle . The mesangial cell population accounts for approximately 30-40% of the total cells in the glomerulus. Mesangial cells can be categorized as either extraglomerular mesangial cells or intraglomerular mesangial cells , based on their relative location to the glomerulus. The extraglomerular mesangial cells are found between
1736-422: The receptor theory of pharmacology stated that a drug's effect is directly proportional to the number of receptors that are occupied. Furthermore, a drug effect ceases as a drug-receptor complex dissociates. Ariëns & Stephenson introduced the terms "affinity" & "efficacy" to describe the action of ligands bound to receptors. In contrast to the accepted Occupation Theory , Rate Theory proposes that
Platelet-derived growth factor receptor A - Misplaced Pages Continue
1792-600: The PDGFRα's kinase activity and hence activating it. For instance, forcing PDGFRα into close proximity of each other by overexpression or with antibodies directed against the extracellular domain. Alternatively, mutations in the kinase domain that stabilize a kinase active conformation result in constitutive activation. Finally, growth factors outside of the PDGFR family (non-PDGFs) activate PDGFRα indirectly. Non-PDGFs bind to their own receptors that trigger intracellular events that de-repress
1848-451: The activation of metabolic pathways leading to increased oxidative stress . This in turn results in the over-production and accumulation of advanced glycosylation end products responsible for enhancing the risk of developing glomerular diseases. Mesangial cells grown on advanced glycosylation end product-modified matrix proteins demonstrate increased production of fibronectin and a decrease in proliferation. These factors eventually lead to
1904-443: The activation of receptors is directly proportional to the total number of encounters of a drug with its receptors per unit time. Pharmacological activity is directly proportional to the rates of dissociation and association, not the number of receptors occupied: As a drug approaches a receptor, the receptor alters the conformation of its binding site to produce drug—receptor complex. In some receptor systems (e.g. acetylcholine at
1960-411: The cell. 4 examples of intracellular LGIC are shown below: Many genetic disorders involve hereditary defects in receptor genes. Often, it is hard to determine whether the receptor is nonfunctional or the hormone is produced at decreased level; this gives rise to the "pseudo-hypo-" group of endocrine disorders , where there appears to be a decreased hormonal level while in fact it is the receptor that
2016-403: The dynamic behavior of receptors have been used to gain understanding of their mechanisms of action. Ligand binding is an equilibrium process. Ligands bind to receptors and dissociate from them according to the law of mass action in the following equation, for a ligand L and receptor, R. The brackets around chemical species denote their concentrations. One measure of how well a molecule fits
2072-664: The filtration pressure of the glomerulus. Mesangial cells have irregular shapes with flattened-cylinder-like cell bodies and processes at both ends containing actin , myosin and actinin , giving mesangial cells contractile properties. The anchoring filaments from mesangial cells to the glomerular basement membrane can alter capillary flow by changing glomerular ultrafiltration surface area. Extraglomerular mesangial cells are in close connection to afferent and efferent arteriolar cells by gap junctions , allowing for intercellular communication. Mesangial cells are separated by intercellular spaces containing extracellular matrix called
2128-414: The following major categories, among others: Membrane receptors may be isolated from cell membranes by complex extraction procedures using solvents , detergents , and/or affinity purification . The structures and actions of receptors may be studied by using biophysical methods such as X-ray crystallography , NMR , circular dichroism , and dual polarisation interferometry . Computer simulations of
2184-439: The growth factor PDGF-B or PDGFRβ do not develop mesangial cells. When mesangial cells are absent the blood vessel becomes a single dilated vessel with up to 100-fold decrease in surface area. The transcription factor for PDGFRβ, Tbx18, is crucial for the development of mesangial cells. Without Tbx18 the development of mesangial cells is compromised and results in the formation of dilated loops. Mesangial cell progenitors are also
2240-438: The half-life of PDGF-activated PDGFRα is approximately 5 min. Enduring activation of PDGFRα (half-life greater than 120 min) occurs when PDGFRα monomers are activated. The importance of PDGFRA during development is apparent from the observation that the majority of mice lacking a functional Pdgfra gene develop a plethora of embryonic defects, some of which are lethal; the mutant mice exhibit defects in kidney glomeruli because of
2296-577: The inhibition of the constitutive activity of the cannabinoid receptor. The GABA A receptor has constitutive activity and conducts some basal current in the absence of an agonist. This allows beta carboline to act as an inverse agonist and reduce the current below basal levels. Mutations in receptors that result in increased constitutive activity underlie some inherited diseases, such as precocious puberty (due to mutations in luteinizing hormone receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors). Early forms of
Platelet-derived growth factor receptor A - Misplaced Pages Continue
2352-418: The kinase activity of PDGFRα monomers. The intracellular events by which non-PDGFs indirectly activate PDGFRα include elevation of reactive oxygen species that activate Src family kinases, which phosphorylate PDGFRα. The mode of activation determines the duration that PDGFRα remains active. The PDGF-mediated mode, which dimerized PDGFRα, accelerates internalization and degradation of activated PDGFRα such that
2408-418: The mesangial matrix that is produced by the mesangial cells. Mesangial matrix provides structural support for the mesangium. Mesangial matrix is composed of glomerular matrix proteins such as collagen IV (α1 and α2 chains), collagen V, collagen VI, laminin A, B1, B2, fibronectin , and proteoglycans . It is unclear whether the mesangial cells originate from mesenchymal or stromal cells . However there
2464-557: The mesangial space by receptor- independent uptake processes of phagocytosis , micro- and macro- pinocytosis , or receptor-dependent processes and then transported along the mesangial stalk. Size, charge, concentration, and affinity for mesangial cell receptors of the macromolecule affects how the macromolecule is removed. Triglycerides may undergo pinocytosis and antibody IgG complexes may lead to activation of adhesion molecules and chemokines by mesangial cells. They also regulate glomerular filtration The expansion of mesangial matrix
2520-472: The neuromuscular junction in smooth muscle), agonists are able to elicit maximal response at very low levels of receptor occupancy (<1%). Thus, that system has spare receptors or a receptor reserve. This arrangement produces an economy of neurotransmitter production and release. Cells can increase ( upregulate ) or decrease ( downregulate ) the number of receptors to a given hormone or neurotransmitter to alter their sensitivity to different molecules. This
2576-747: The phase II trial, (NCT01185964). In addition, the European Medicines Agency granted conditional approval for olaratumab in this indication in November 2016 following a review under the EMA's Accelerated Assessment Program. Gain-of-function H3K27M mutations in protein histone H3 lead to inactivation of polycomb repressive complex 2 (PRC2) methyltransferase and result in global hypo methylation of H3K27me3 and transcriptional derepression of potential oncogenes . About 40% of these mutation are associated with gain of function or amplifications mutations in
2632-546: The platelet-derived growth factor family. Activation of PDGFRA requires de-repression of the receptor's kinase activity. The ligand for PDGFRα (PDGF) accomplishes this in the course of assembling a PDGFRα dimer. Four of the five PDGF isoforms activate PDGFRα (PDGF-A, PDGF-B, PDGF-AB and PDGF-C). The activated receptor phosphorylates itself and other proteins, and thereby engages intracellular signaling pathways that trigger cellular responses such as migration and proliferation. There are also PDGF-independent modes of de-repressing
2688-458: The process of tubuloglomerular feedback and urine formation. Damage to mesangial cells using Thy 1-1 antibody specific to mesangial cells causes the vasoconstriction of arterioles mediated by tubuloglomerular feedback to be lost. Mesangial cells can contract and relax to regulate capillary flow. This is regulated by vasoactive substances . Contraction of mesangial cells is dependent on cell membrane permeability to calcium ions and relaxation
2744-413: The receptor. Numerous studies using it to treat soft tissue sarcomas including GIST are ongoing. Studies on GIST have focused on inoperable, metastatic, and/or recurrent disease and have tested olagatumab with Doxorubicin versus doxorubicin along. The US FDA granted approval for the use of olaratumab-dcoxorbicin therapy of soft tissue sarcomas under its Accelerated Approval Program based on the results of
2800-566: The same origin as supporting cells such as pericytes and vascular smooth muscle cells, or even be a type of specialised vascular smooth muscle cell. During development mesangial cells are important in the formation of convoluted capillaries allowing for efficient diffusion to occur. Endothelial precursor cells secrete platelet-derived growth factor (PDGF)-B and mesangial cells have receptors for PDGF. This induces mesangial cells to attach to endothelial cells causing developing blood vessels to loop resulting in convoluted capillaries. Mice lacking
2856-438: The signal to be incorporated into another biochemical pathway. Receptor proteins can be classified by their location. Cell surface receptors , also known as transmembrane receptors, include ligand-gated ion channels , G protein-coupled receptors , and enzyme-linked hormone receptors . Intracellular receptors are those found inside the cell, and include cytoplasmic receptors and nuclear receptors . A molecule that binds to
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#17330853804712912-597: The table below. The chief neurotransmitters are glutamate and GABA; other neurotransmitters are neuromodulatory . This list is by no means exhaustive. Enzyme linked receptors include Receptor tyrosine kinases (RTKs), serine/threonine-specific protein kinase, as in bone morphogenetic protein and guanylate cyclase, as in atrial natriuretic factor receptor. Of the RTKs, 20 classes have been identified, with 58 different RTKs as members. Some examples are shown below: Receptors may be classed based on their mechanism or on their position in
2968-471: The thickening of the glomerular basement membrane, mesangial matrix expansion then glomerulosclerosis and fibrosis . Mesangial pathologies may also develop during the early phase of diabetes. Glomerular hypertension causes mesangial cells to stretch which causes induced expression of GLUT1 leading to increased cellular glucose. The repetition of stretching and relaxation cycle of mesangial cells due to hypertension increases mesangial cell proliferation and
3024-598: The tract's epithelium cells. GIST tumors occur throughout the GI tract but most (66%) occur in the stomach and when developing there have a lower malignant potential than GIST tumors found elsewhere in the GI tract. The most common PDGFRA mutations found in GIST tumors occur in exon 18 and are thought to stabilize PDGFRA's tyrosine kinase in an activated conformation. A single mutation, D842V, in this exon accounts for >70% of GIST tumors. The next most common GIST tumor mutation occurs in exon 18, accounts for <1% of GISTs tumors, and
3080-411: The treatment of diseases caused by FIP1L1-PDGFRA fusion genes . Activating mutations in PDGFRA are also involved in the development of 2–15% of gastrointestinal stromal tumors (GISTs), which is the most common mesenchymal neoplasm of the gastrointestinal tract . GIST tumors are sarcomas derived from the GI tract's connective tissue whereas most GI tract tumors are adenocarcinomas derived from
3136-441: The type of malignancy formed likely reflects the specific type(s) of hematopoietic stem cells that bear the mutation. The PDGFRA gene may also mutate through any one of several chromosome translocations to create fusion genes which, like the Fip1l1-PDGFRA fusion gene, encode a fusion protein that possesses continuously active PDGFRA-related tyrosine kinase and causes myeloid and/or lymphoid malignancies. These mutations, including
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