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Platelet-derived growth factor receptor beta is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''PDGFRB''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. Mutations in PDGFRB are mainly associated with the clonal eosinophilia class of malignancies.


Gene

The ''PDGFRB'' gene is located on human chromosome 5 at position q32 (designated as 5q32) and contains 25
exons 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 seque ...
. The gene is flanked by the genes for granulocyte-macrophage colony-stimulating factor and
Colony stimulating factor 1 receptor Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), is a cell-surface protein encoded by the human ''CSF1R'' gene (known also as c-FMS). C ...
(also termed macrophage-colony stimulating factor receptor), all three of which may be lost together by a single deletional mutation thereby causing development of the 5q-syndrome. Other genetic abnormalities in ''PDGFRB'' lead to various forms of potentially malignant bone marrow disorders: small deletions in and chromosome translocations causing fusions between ''PDGFRB'' and any one of at least 30 genes can cause Myeloproliferative neoplasms that commonly involve
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 ...
, eosinophil-induced organ injury, and possible progression to aggressive leukemia (see blow).


Structure

The PDGFRB gene encodes a typical
receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...
, which belongs to the type III tyrosine kinase receptor (RTK) family and is structurally characterized by five extracellular immunoglobulin-like domains, a single membrane-spanning helix domain, an intracellular juxtamembrane domain, a split tyrosine kinase domain and a carboxylic tail. In the absence of ligand, PDGFRβ adopts an inactive conformation in which the activation loop folds over the catalytic site, the juxtamembrane region over a loop occluding the active site and the carboxy-terminal tail over the kinase domain. Upon PDGF binding the dimerization of receptor releases the inhibitory conformations due to auto-phosphorylation of regulatory tyrosine residues in trans fashion. Tyrosine residues 857 and 751 are major phosphorylation sites for the activation of PDGFRβ. The molecular mass of the mature, glycosylated PDGFRβ protein is approximately 180 kDa.


Modes of activation

Activation of PDGFRβ requires de-repression of the receptor's kinase activity. The ligand for PDGFRβ (PDGF) accomplishes this in the course of assembling a PDGFRβ dimer. Two of the five PDGF isoforms activate PDGFRβ (PDGF-B and PDGF-D). 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 PDGFRβ's kinase activity and hence activating it. For instance, forcing PDGFRβ 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. Unlike PDGFRα, PDGFRβ cannot be indirectly activated. This is because PDGFRβ recruits RasGAP and thereby attenuates Ras/PI3K activity, which is required to engage a feed-forward loop that is responsible for this mode of activation.


Role in physiology/pathology

The phenotype of knock out mice demonstrates that PDGFRB is essential for vascular development, and that PDGFRB is responsible for activating PDGFRβ during embryogenesis. Eliminating either PDGFRB, or PDGF-B reduces the number of pericytes and vascular smooth muscle cells, and thereby compromises the integrity and/or functionality of the vasculature in multiple organs, including the brain, heart, kidney, skin and eye. In vitro studies using cultured cells indicate that endothelial cells secrete PDGF, which recruits PDGFRβ-expressing pericytes that stabilize nascent blood vessels. Mice harboring a single activated allele of PDGFRB show a number of postnatal phenotypes including reduced differentiation of aortic vascular smooth muscle cells and brain pericytes. Similarly, differentiation of adipose from pericytes and mesenchymal cells is suppressed. Misregulation of the PDGFRβ's kinase activity (typically activation) contributes to endemic diseases such as cancer and cardiovascular disease.


PDGFRB mutations


5q- Syndrome

Human chromosome 5 deletions that remove three adjacent genes, those for granulocyte-macrophage colony-stimulating factor, PDGFRB, and
Colony stimulating factor 1 receptor Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), is a cell-surface protein encoded by the human ''CSF1R'' gene (known also as c-FMS). C ...
, cause the Chromosome 5q deletion syndrome (5q- syndrome). This syndrome is a unique type of
myelodysplastic syndrome 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 ...
characterized by a prolonged disease course, a low rate of transformation to an aggressive form 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 ...
, and an
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
which in many patients is profound, refractory to traditional therapies (e.g. iron supplements,
Erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in th ...
), and requiring maintenance red blood cell transfusions. The disease is treated with a chemotherapy drug,
lenalidomide Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is used after at least one other treatment and gen ...
.


''PDGFRB'' Translocations

Human chromosome translocations between the ''PDGFRB'' gene and at least any one of 30 genes on other chromosomes lead to
myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + '' -oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue o ...
and/or
lymphoid The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...
neoplasms that are many ways similar to the neoplasm caused by the fusion of the
PDGFRA 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 140a, is a receptor located on the surface of a wide range of cell types. This re ...
(i.e. platelet derived growth factor receptor A or alpha-type-platelet derived growth factor receptor) gene with the FIP1L1 gene (see FIP1L1-PDGFRA fusion gene. The most common of these rare mutations is the translocation of ''PDGFRB'' gene with the '' ETV6'' gene (also termed ''ETS variant gene 6'').


= ''PDGFRB''-''ETV6'' translocations

= The ''ETV6'' gene codes for a transcription factor protein that in mice appears to be required for
hematopoiesis Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells ...
and maintenance of the developing vascular network. The gene is located on human chromosome 12 at the p13 position, consists of 14
exons 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 seque ...
, and is well-known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital
fibrosarcoma Fibrosarcoma (fibroblastic sarcoma) is a malignant mesenchymal tumour derived from fibrous connective tissue and characterized by the presence of immature proliferating fibroblasts or undifferentiated anaplastic spindle cells in a storiform pat ...
. Translocations between it and the ''PDGFRB'' gene, notated as t(5;12)(q33;p13), yield a ''PDGFRB-ETV6'' fused gene that encodes a
fusion protein Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this '' fusion gene'' ...
, PDGFRB-ETV6. This chimeric protein, unlike the PDGFRB protein: a) has continuously active PDGFRB-mediated
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 ...
due to its forced dimerization by the PNT protein binding domain of the ETV6 protein; b) is highly stable due to its resistance to ubiquitin-
Proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by whi ...
degradation; and c) therefore over-stimulates
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 such as STAT5,
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
, and Extracellular signal-regulated kinases which promote cell growth and proliferation. This continuous signaling, it is presumed, leads to the development of myeloid and/or lymphoid neoplasms that commonly include increased numbers of blood born and tissue
eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s, eosinophil-induced organ and tissue injury, and possible progression to aggressive form of leukemia. PDGFRB-ETV6 fusion protein-induced neoplasms often present with features that would classify them as
Chronic myelomonocytic leukemia Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are ...
s,
juvenile myelomonocytic leukemia Juvenile myelomonocytic leukemia (JMML) is a serious chronic leukemia (cancer of the blood) that affects children mostly aged 4 and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic myeloid leukemia (JC ...
,
Atypical ''Atypical'' is an American comedy-drama television series created by Robia Rashid for Netflix. It focuses on the life of 18-year-old Sam Gardner ( Keir Gilchrist), who is on the autism spectrum. The first season was released on August 11, 201 ...
or Philadelphia chromosome negative chronic myeloid leukemias,
myelodysplastic syndrome 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 ...
s,
acute myelogenous leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may inclu ...
s, or
acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruis ...
s. The disease is now classified by the World Health Organization as one form of clonal eosinophilia. It is critical that the PDGFRB-ETV6 fusion protein-driven disease be diagnostically distinguished from many of the just cited other diseases because of its very different treatment. Patients with the PDGFRB-ETV6 fusion protein-driven disease are more often adult males but rarely children. They present with
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
, increases in blood eosinophils and monocytes,
splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulatin ...
, and, less often, lymphadenopathy.
Bone marrow examination Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy (often called trephine biopsy) and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditi ...
may reveal cellular features similar to that seen in the aforementioned diseases. Diagnosis is may by conventional cytogenetic examination of blood or bone marrow cells to test for PDGFRB rearrangements using Fluorescence in situ hybridization or to test for the fused ''FDGFRB-ATV6'' fluorescence in situ hybridization and/or
Real-time polymerase chain reaction A real-time polymerase chain reaction (real-time PCR, or qPCR) is a laboratory technique of molecular biology based on the polymerase chain reaction (PCR). It monitors the amplification of a targeted DNA molecule during the PCR (i.e., in real ...
using appropriate nucleotide probes. These patients, unlike many patients with similarly appearing neoplasms, respond well 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 drug often causes long-term complete hematological and cytogenic remissions as doses well below those used to treat
chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumul ...
. Primary or acquired
drug resistance Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is ...
to this drug is very rare. Additional adjuvant
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
may be necessary if a patients disease is unresponsive to tyrosine kinase inhibitor therapy and/or progresses to more aggressive disease phase similar to that seen in the blast crisis of chronic myelogenous leukemia.


= Other ''PDGFRB'' translocations

= The ''PDGFRB'' gene has been found to fuse with at least 36 other genes to form fusion genes that encode chimeric proteins that are known or presumed to possess: a) continuously active PDGFRB-derived tyrosine kinase activity; b) the ability to continuously stimulate the growth and proliferation of hematological stem cells; and c) the ability to cause myeloid and lymphoid neoplasms that commonly but not always are associated with eosinophilia. In all instances, these gene fusion diseases are considered types of clonal eosinophilia with recommended treatment regimens very different than those of similar hematological malignancies. The genes fusing to ''PDGFRB'', their chromosomal location, and the notations describing their fused genes are given in the following table. Similar to ''PDGFRB-ETV6'' translocations, these translocations are generally in-frame and encode for fusion proteins with their PDGFRB-derived tyrosine kinase being continuously active and responsible for causing the potentially malignant growth of its myeloid and/or lymphoid harboring cells. Patients are usually middle-aged men. They commonly present with anemia, eosinophilia, monocytosis, and splenomegaly and have their disease classified as chronic myelomonocytic leukemia, atypical chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, acute myelogenous leukemia, acute lymphoblastic leukemia, or T lymphoblastic lymphoma. Diagnosis relies on cytogenetic analyses to detect breakpoints in the long arm of chromosome 5 by Fluorescence in situ hybridization. These patients usually 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.


= Primary familial brain calcification

= Primary familial brain calcification (see
Fahr's syndrome Primary Indiana familial brain calcification Initial Posting: April 18, 2004; Last Update: August 24, 2017. (PFBC), also known as familial idiopathic basal ganglia calcification (FIBGC) and Fahr's disease, is a rare, genetically dominant, inher ...
) is a rare disease involving bilateral calcifications in the brain, predominantly in basal ganglia but also cerebellum, thalamus, and brainstem in patients presenting with diverse neurologic (e.g. movement disorders, parkinsonism, seizures, headache) features and psychiatric (e.g. cognitive impairment, mood disorders, psychotic symptoms, and obsessive-compulsive) disturbances. In a minority of cases, the disease is associated with apparent
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
loss of function mutations in ''PDGFRB'' or the gene which encodes a ligand that simulates PDGFRB,
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 ...
, ''PDGFB''. PDGFRB is extensively expressed in the neurons, chorioid plexus, vascular smooth muscle cells, and pericytes of the human brain, particularly the basal ganglia and the dentate nucleus. It is proposed that signal transduction through PDGFRB maintains blood–brain barrier integrity and that loss of the PDGFRB receptor or its ligand, PDGFB, disrupts the blood–brain barrier, subsequently promoting (peri)vascular calcium deposition and thereby causing the dysfunction and death of neurons.


Interactions

PDGFRB 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, * Grb2, *
NCK1 Cytoplasmic protein NCK1 is a protein that in humans is encoded by the ''NCK1'' gene. Gene The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated from ...
, * NCK2, * PDGFR-α, *
PTPN11 Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in huma ...
, *
RAS p21 protein activator 1 RAS p21 protein activator 1 or RasGAP (Ras GTPase activating protein), also known as RASA1, is a 120- kDa cytosolic human protein that provides two principal activities: * Inactivation of Ras from its active GTP-bound form to its inactive GDP-bo ...
, *
SHC1 SHC-transforming protein 1 is a protein that in humans is encoded by the ''SHC1'' gene. SHC has been found to be important in the regulation of apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of pro ...
and * Sodium-hydrogen antiporter 3 regulator 1.


Notes


See also

*
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 ...
*
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 ...
* Kosaki overgrowth syndrome


References


Further reading

* *


External links

* {{Portal bar, Biology, border=no Clusters of differentiation Genes on human chromosome 12 Tyrosine kinase receptors