PDGFRB
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| Location (UCSC) | Chr 5: 150.11 – 150.16 Mb | Chr 18: 61.18 – 61.22 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
Platelet-derived growth factor receptor beta is a
Gene
The PDGFRB gene is located on
Structure
The PDGFRB gene encodes a typical receptor tyrosine kinase, 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.[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.
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.[9][10]
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.[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 and mesenchymal 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]
PDGFRB mutations
5q- Syndrome
Human chromosome 5 deletions that remove three adjacent genes, those for
PDGFRB Translocations
Human chromosome translocations between the PDGFRB gene and at least any one of 30 genes on other chromosomes lead to
PDGFRB-ETV6 translocations
The ETV6 gene codes for a transcription factor protein that in mice appears to be required for
PDGFRB-ETV6 fusion protein-induced neoplasms often present with features that would classify them as
Patients with the PDGFRB-ETV6 fusion protein-driven disease are more often adult males but rarely children. They present with
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
| 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 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 therapy.[6][22][33]
Primary familial brain calcification
Primary familial brain calcification (see
Interactions
PDGFRB has been shown to
Notes
Wikidata Q39166181 . |
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000113721 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024620 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "PDGFRB platelet derived growth factor receptor beta [Homo sapiens (human)] - Gene - NCBI".
- ^ PMID 28028030.
- PMID 23906712.
- PMID 1709159.
- PMID 24190966.
- PMID 25733681.
- PMID 7958864.
- PMID 9211853.
- PMID 9693135.
- PMID 7958863.
- PMID 9916126.
- PMID 21664579.
- PMID 18483217.
- PMID 24359404.
- S2CID 17343813.
- PMID 16735711.
- ^ "ETV6 ETS variant 6 [Homo sapiens (human)] - Gene - NCBI".
- ^ PMID 26276769.
- PMID 27069254.
- ^ a b "WDR48 WD repeat domain 48 [Homo sapiens (human)] - Gene - NCBI".
- ^ "PRKG2 protein kinase cGMP-dependent 2 [Homo sapiens (human)] - Gene - NCBI".
- ^ "CEP85L centrosomal protein 85 like [Homo sapiens (human)] - Gene - NCBI".
- ^ "CCDC6 coiled-coil domain containing 6 [Homo sapiens (human)] - Gene - NCBI".
- ^ "CAPRIN1 cell cycle associated protein 1 [Homo sapiens (human)] - Gene - NCBI".
- ^ "NIN ninein [Homo sapiens (human)] - Gene - NCBI".
- ^ "CCDC88C coiled-coil domain containing 88C [Homo sapiens (human)] - Gene - NCBI".
- ^ "BIN2 bridging integrator 2 [Homo sapiens (human)] - Gene - NCBI".
- ^ "DTD1 D-tyrosyl-tRNA deacylase 1 [Homo sapiens (human)] - Gene - NCBI".
- S2CID 42668440.
- PMID 25686319.
- PMID 28162874.
- PMID 10733900.
- PMID 10066366.
- ^ PMID 10026169.
- PMID 7935391.
- PMID 9362449.
- PMID 1333047.
- PMID 9737977.
- PMID 11027258.
- PMID 7523122.
- PMID 2542288.
- PMID 11266449.
- PMID 7691811.
- PMID 10697503.
- PMID 11896619.
- PMID 8195171.
- PMID 11046132.
Further reading
- Hart CE, Bowen-Pope DF (1990). "Platelet-derived growth factor receptor: current views of the two-subunit model". J. Invest. Dermatol. 94 (6 Suppl): 53S–57S. PMID 2161888.
- Steer EJ, Cross NC (2002). "Myeloproliferative disorders with translocations of chromosome 5q31-35: role of the platelet-derived growth factor receptor Beta". Acta Haematol. 107 (2): 113–22. S2CID 202646911.
External links
- CD140B+Antigen at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
