PDGFRA, i.e. platelet-derived growth factor receptor A, also termed PDGFRα, i.e. platelet-derived growth factor receptor α, or CD140a i.e.
Cluster of Differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
140a, is a
receptor
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
located on the surface of a wide range of cell types. This receptor binds to certain
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...
s of
platelet-derived growth factor
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood v ...
s (PDGFs) and thereby becomes active in stimulating
cell signaling
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
pathways that elicit responses such as
cellular growth and
differentiation. The receptor is critical for
the development of certain tissues and organs during embryogenesis and for the maintenance of these tissues and organs, particularly
hematologic tissues, throughout life.
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s in the gene which codes for PDGFRA, i.e. the ''PDGFRA'' gene, are associated with an array of clinically significant
neoplasms
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
, notably ones of the
clonal hypereosinophilia class of malignancies, as well as
gastrointestinal stromal tumor
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs arise in the smooth muscle pacemaker interstitial cell of Cajal, or similar cells. They are defined as tumors whose behavior ...
s (GISTs).
Overall structure
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 the platelet-derived growth factor family.
Modes of activation
Activation of PDGFRα 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 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 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 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.
Role in physiology/pathology
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 a lack of
mesangial cell
Mesangial cells are specialised cells in the kidney that make up 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 ...
s 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 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
mesoderm
The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical Emb ...
al tissues, e.g., blood cells, connective tissue, and mesangial cells.
Clinical significance
PDGFRA mutations
Myeloid and lymphoid cells
Somatic mutations that cause the fusion of the ''PDGFRA'' gene with certain other genes occur in
hematopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within ...
s and cause 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
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
. They thereby continuously stimulate cell growth and proliferation and lead to the development of
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
s,
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...
s, and
myelodysplastic syndromes
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
that are commonly associated with
hypereosinophilia and therefore regarded as 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 a FIP1L1-PDGFRA protein that causes: a) chronic
eosinophilia
Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds . Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 x 109/ L (i.e. 1,500/ μL). The hypereosinophilic sy ...
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
T-lymphoblastic leukemia/lymphoma (WHO 2008), previously labeled precursor T-lymphoblastic leukemia/lymphoma (WHO 2001) is a form of lymphoid leukemia and lymphoma in which too many T-cell lymphoblasts (immature white blood cells) are found in th ...
associated with eosinophilia; d)
myeloid sarcoma with eosinophilia (see
''FIP1L1-PDGFRA'' fusion genes); or e) mixtures of these presentations. Variations in 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 the ''Fip1l1-PDGFRA'' mutation, along with the chromosomal location of ''PDGFRAs 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; 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
Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...
therapy as described for the treatment of diseases caused by ''FIP1L1-PDGFRA'' fusion genes.[
]
Gastrointestinal tract
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
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
. GIST tumors are sarcoma
A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal ( connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sar ...
s derived from the GI tract's connective tissue whereas most GI tract tumors are adenocarcinoma
Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, o ...
s derived from the tract's epithelium
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
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
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
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 is a deletion of codon
The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
s 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
Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...
, the most common mutation, D842V, as well as some very rare mutations are resistant to this drug: median overall survival 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, 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
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ...
designed to bind to human PDGFRα with high affinity and block PDGF-AA, PDGF-BB, and PDGF-CC ligands from binding to 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 the phase II trial, (NCT01185964). In addition, the European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...
granted conditional approval for olaratumab in this indication in November 2016 following a review under the EMA's Accelerated Assessment Program.
Nervous system
Gain-of-function H3K27M mutations in protein histone H3
Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'beads on a st ...
lead to inactivation of polycomb repressive complex 2 (PRC2) methyltransferase
Methyltransferases are a large group of enzymes that all Methylation, methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which co ...
and result in global hypomethylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...
of H3K27me3 and transcriptional derepression In genetics and cell biology, repression is a mechanism often used to decrease or inhibit the expression of a gene. Removal of repression is called derepression. This mechanism may occur at different stages in the expression of a gene, with the resu ...
of potential oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s. About 40% of these mutation are associated with gain of function or amplifications mutations in the ''PDGFRA'' gene in cases of pediatric diffuse Glioma
A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours.
Signs and symptoms
...
s of the pons
The pons (from Latin , "bridge") is part of the brainstem that in humans and other bipeds lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum.
The pons is also called the pons Varolii ("bridge of Va ...
. 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
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...
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.[https://clinicaltrials.gov/ct2/results?term=+imatinib+and+glioma&Search=Search]
Interactions
PDGFRA has been shown to interact
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with:
* CRK,
* Caveolin 1,
* Cbl gene,
* PDGFC,
* PDGFR-β,
* PLCG1, and
* Sodium-hydrogen antiporter 3 regulator 1.
Notes
See also
* Platelet-derived growth factor receptor
Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular ...
* Clonal eosinophilia
References
Further reading
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Tyrosine kinase receptors