Platelet-derived growth factor receptor beta is aprotein that in humans is encoded by thePDGFRBgene. Mutations in PDGFRB are mainly associated with theclonal eosinophilia class of malignancies.
ThePDGFRB gene is located onhuman chromosome 5 at position q32 (designated as 5q32) and contains 25exons. The gene is flanked by the genes forgranulocyte-macrophage colony-stimulating factor andColony stimulating factor 1 receptor (also termed macrophage-colony stimulating factor receptor), all three of which may be lost together by a singledeletional mutation thereby causing development of the5q-syndrome.[5] Other genetic abnormalities inPDGFRB lead to various forms of potentially malignant bone marrow disorders: small deletions in and chromosometranslocations causing fusions betweenPDGFRB and any one of at least 30 genes can causeMyeloproliferative neoplasms that commonly involveeosinophilia, eosinophil-induced organ injury, and possible progression to aggressive leukemia (see blow).[6]
The PDGFRB gene encodes a typicalreceptor tyrosine kinase, which belongs to the type IIItyrosine 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.[7] 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.[8]
The molecular mass of the mature, glycosylated PDGFRβ protein is approximately 180 kDa.
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.[9][10]
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.[11][12][13][14]
In vitro studies using cultured cells indicate that endothelial cells secrete PDGF, which recruits PDGFRβ-expressing pericytes that stabilize nascent blood vessels.[15] 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 andmesenchymal cells is suppressed.[16] Misregulation of the PDGFRβ's kinase activity (typically activation) contributes to endemic diseases such as cancer and cardiovascular disease.[17][18][19]
Human chromosome 5 deletions that remove three adjacent genes, those forgranulocyte-macrophage colony-stimulating factor, PDGFRB, andColony stimulating factor 1 receptor, cause theChromosome 5q deletion syndrome (5q- syndrome). This syndrome is a unique type ofmyelodysplastic syndrome characterized by a prolonged disease course, a low rate of transformation to an aggressive form ofleukemia, and ananemia which in many patients is profound, refractory to traditional therapies (e.g. iron supplements,Erythropoietin), and requiring maintenance red blood cell transfusions. The disease is treated with achemotherapy drug,lenalidomide.[5][20]
Human chromosome translocations between thePDGFRB gene and at least any one of 30 genes on other chromosomes lead tomyeloid and/orlymphoid neoplasms that are many ways similar to the neoplasm caused by the fusion of thePDGFRA (i.e. platelet derived growth factor receptor A or alpha-type-platelet derived growth factor receptor) gene with theFIP1L1 gene (seeFIP1L1-PDGFRA fusion gene. The most common of these rare mutations is the translocation ofPDGFRB gene with theETV6 gene (also termedETS variant gene 6).
TheETV6 gene codes for a transcription factor protein that in mice appears to be required forhematopoiesis and maintenance of the developing vascular network. The gene is located on human chromosome 12 at the p13 position, consists of 14exons, and is well-known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenitalfibrosarcoma.[21] Translocations between it and thePDGFRB gene, notated as t(5;12)(q33;p13), yield aPDGFRB-ETV6 fused gene that encodes afusion protein, PDGFRB-ETV6. This chimeric protein, unlike the PDGFRB protein:a) has continuously active PDGFRB-mediatedtyrosine kinase 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 degradation; andc) therefore over-stimulatescell signaling pathways such asSTAT5,NF-κB, andExtracellular 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 tissueeosinophils, eosinophil-induced organ and tissue injury, and possible progression to aggressive form of leukemia.[22]
PDGFRB-ETV6 fusion protein-induced neoplasms often present with features that would classify them asChronic myelomonocytic leukemias,juvenile myelomonocytic leukemia,Atypical orPhiladelphia chromosome negative chronic myeloid leukemias,myelodysplastic syndromes,acute myelogenous leukemias, oracute lymphoblastic leukemias. The disease is now classified by the World Health Organization as one form ofclonal eosinophilia.[23] 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 withanemia, increases in blood eosinophils and monocytes,splenomegaly, and, less often, lymphadenopathy.Bone marrow examination may reveal cellular features similar to that seen in the aforementioned diseases. Diagnosis is may by conventionalcytogenetic examination of blood or bone marrow cells to test for PDGFRB rearrangements usingFluorescence in situ hybridization or to test for the fusedFDGFRB-ATV6 fluorescence in situ hybridization and/orReal-time polymerase chain reaction using appropriate nucleotide probes.[22] These patients, unlike many patients with similarly appearing neoplasms, respond well to the tyrosine kinase inhibitor,imatinib. The drug often causes long-term complete hematological and cytogenic remissions as doses well below those used to treatchronic myelogenous leukemia. Primary or acquireddrug resistance to this drug is very rare. Additional adjuvantchemotherapy may be necessary if a patient's disease is unresponsive to tyrosine kinase inhibitor therapy and/or progresses to more aggressive disease phase similar to that seen in theblast crisis of chronic myelogenous leukemia.[22][6]
ThePDGFRB 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; andc) 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 ofclonal eosinophilia with recommended treatment regimens very different than those of similar hematological malignancies. The genes fusing toPDGFRB, their chromosomal location, and the notations describing their fused genes are given in the following table.[6][22]
| Gene | locus | notation | gene | locus | notation | Gene | locus | notation | gene | locus | notation | gene | locus | notation | gene | locus | notation | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| TPM3 | 1q21 | t(1;5)(q21;q32) | PDE4DIP | 1q22 | t(1;5)(q22;q32) | SPTBN1 | 2p16 | t(2;5)(p16;q32) | GOLGA4 | 3p21-25 | t(3;5)(p21-25;q31-35) | WRD48[24] | 3p21-22 | t(1;3;5)(p36;p21;q32) | PRKG2[25] | 4q21 | t(4;5)(p21;q32) | |||||
| CEP85L[26] | 6q22 | t(5;6)(q32;q22) | HIP1 | 7q11 | t(5;7)(q32;q11) | KANK1 | 9q24 | t(5;9)(q32;q24) | BCR | 9q34 | t(5;9)(q32;q34) | CCDC6 | 10q21 | t(5;10)(q32;q21 | H4(D10S170)[27] | 10q21.2 | t(5;10)(q32;q21.2) | |||||
| GPIAP1[28] | 11p13 | multiple | ETV6 | 12p13 | t(5;12)q32;p13) | ERC1 | 12p13.3 | t(5;12)(q32;p13.3) | GIT2 | 12q24 | t(5;12)(q31-33;q24) | NIN[29] | 14q24 | t(5;14)(q32;q24 | TRIP11 | 14q32 | t(5;14)(q32;q32) | |||||
| CCDC88C[30] | 14q32 | t(5;14)(q33;q32) | TP53BP1 | 15q22 | t(5;15)q33;22) | NDE1 | 16p13 | t(5;16)(q33;p13) | SPECC1 | 17p11 | t(5;17)(q32;p11.2) | NDEL1 | 17p13 | t(5;17)(q32;p13) | MYO18A | 17q11.2 | t(5;17)(q32;q11.2) | |||||
| BIN2[31] | 12q13 | t(5;12)(q32;q13) | COL1A1 | 17q22 | t(5;17)q32;q22) | DTD1[32] | 20p11 | t(5;20)(q32;p11) | CPSF6 | 12q15 | t(5;12)(q32;q15) | RABEP1 | 17p13 | t(5;17)(q32;p13) | MPRIP | 17p11 | t(5;17)(q32;p11) | |||||
| SPTBN1 | 2p16 | t(5;2)(q32;p16) | WDR48[24] | 3p22 | t(5;3)q32;p22) | GOLGB1 | 3q12 | t(3;5)(q12;q32) | DIAPH1 | 5q31 | t(5;5)(q32;q31) | TNIP1 | 5q33 | t(5;5)(q32;q33) | SART3 | 12q23 | t(5;12)(q32;q23) |
Similar toPDGFRB-ETV6 translocations, these translocations are generallyin-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, orT lymphoblastic lymphoma. Diagnosis relies on cytogenetic analyses to detect breakpoints in the long arm of chromosome 5 byFluorescence in situ hybridization. These patients usually respond well toimatinib therapy.[6][22][33]
Primary familial brain calcification (seeFahr's syndrome) 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 apparentautosomal dominant loss of function mutations inPDGFRB or the gene which encodes a ligand that simulates PDGFRB,Platelet-derived growth factor,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.[34][35]
PDGFRB has been shown tointeract with:
 | The 2017 version of this article was updated by an external expert under a dual publication model. The correspondingacademic peer reviewed article was published inGene and can be cited as: Andrius Kazlauskas (3 March 2017)."PDGFs and their receptors".Gene. Gene Wiki Review Series.614:1–7.doi:10.1016/J.GENE.2017.03.003.ISSN 0378-1119.PMC 6728141.PMID 28267575.Wikidata Q39166181. |
