PDGFRA (platelet-derived growth factor receptor, alpha polypeptide)

2014-06-01   Adriana Zamecnikova , Soad Al Bahar 

Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh, 70653, Kuwait


Atlas Image
PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) Hybridization with Vysis 4q12 Tri-Color break apart rearrangement probe (Abbott Molecular, US) showing PDGFRA on 4q12 (red-green-aqua signal) - Courtesy Adriana Zamecnikova.



The gene encoding the α-subunit of the PDGFRA maps to band q12 of chromosome 4. The gene contains 23 exons spanning about 65 kb. The first noncoding exon is followed by a large intron of approximately 23 kb (Gronwald et al., 1990; Kawagishi et al., 1995). An important paralog of PDGFRA is FLT4.


6.4-kb transcript; coexpressed with the 5.3-kb PDGF receptor mRNA.



Size: 1089 amino acids; molecular weight: 122670 Da.
Subunit: Interacts with dimeric PDGFA, PDGFB and/or PDGFC; heterodimers with PDGFRB. Present in an inactive conformation as a monomer in the absence of bound ligand.


PDGFR expression is characteristic of various mesodermal derivatives; specially expressed in the urinary tracts and in male and female genitals.


Subcellular location: cell membrane.


Member of the type III class of tyrosine kinase receptors which also includes c-KIT, FLT3 and the macrophage-colony-stimulating factor receptor; characterized by five immunoglobuline-like extracellular domains; a single-spanning transmembrane domain and an intracellular split kinase domain, connected by a flexible polypeptide insert; structurally homologous to c-KIT. PDGFA has transmembrane receptor protein tyrosine kinase activity and acts as a cell-surface receptor for members of the platelet-derived growth factor family: PDGFA, PDGFB and PDGFC, which are mitogens for fibroblasts and cells of mesenchymal origin origin. It plays an essential role in the regulation of many biological processes including cell proliferation, survival, differentiation and cell migration. Plays an important role in embryonic development, in the adult control tissue homeostasis in various organs including kidney, epidydimis, lung and pancreas; required for normal development of intestinal villi in the gastrointestinal tract, plays a role in platelet activation, wound healing and angiogenesis (Demoulin et al., 2012; Heldin et al., 2013).
Regulation: Function as homo- and/or heterodimers depending on the cell type; activated by ligand-induced dimerization and autophosphorylation on specific tyrosine residues upon binding. Activation of the intracellular kinase activity of the receptor leads to creation of docking sites for signal transduction molecules. Subsequent phosphorylation of its substrates initiates a variety of signal transduction cascades that promotes cell proliferation, survival and migration through the PI3K-AKT-mTOR and RAS-MAPK pathways as well as promotes activation of STAT family members (JAK/STAT) (Demoulin et al., 2012).



Mutations in the PDGFRA gene contribute to the pathophysiology of various diseases such as atherosclerosis, abnormalities of the tubal neural development and fibrotic diseases. In cancer, activating point mutations, gene amplifications and chromosomal rearrangements including gene fusions and chromosomal deletions have been found in certain malignancies. These include hematological malignancies such as acute myeloid leukemia, atypical chronic myelogenous leukemia, chronic myelomonocytic leukemia, eosinophilic disorders and mastocytosis (Gotlib et al., 2008). PDGFRA mutations also have been described in somatic and familial gastrointestinal stromal tumors, synovial sarcomas, glioblastoma, malignant peripheral nerve sheath tumors, melanoma and a in a variety of other cancers (Chompret et al., 2004; Heinrich et al., 2003).

Implicated in

Entity name
Gastrointestinal stromal tumor (GIST)
Activating mutations of PDGFRA are found in 5-8% of patients with gastrointestinal stromal tumors (GISTs) but their frequency increases to 30% to 40% in gastric GISTs lacking KIT mutations (Corless et al., 2005; Lasota et al., 2008). The majority of these mutations are "substitution missense", that can arise by various mechanisms (Figure 1). These include mutation hot spots in exon 18 of the PDGFRA gene such as the Asp-to-Val substitution at codon 842 (D842V) encoding the activation loop. Other activating mutations are less frequent such as mutations in exons 12 encoding the juxtamembrane domain and in exon 14 encoding the tyrosine kinase 1 domain of PDGFRA (Chompret et al., 2004; Heinrich et al., 2003). PDGFRA mutations except for D842V in exon 18 are sensitive to imatinib inhibition. However, despite initial clinical responses to tyrosine kinase inhibitors (imatinib, nilotinib, sorafenib and sunatinib), the majority of these patient develops resistance to the drug limiting the long-term benefit of tyrosine kinase inhibitors in this group of patients (Gramza et al., 2009; Pierotti et al., 2011).
The D842V mutation results in an amino acid substitution at position 842 in PDGFRA, from an aspartic acid (D) to a valine (V). This mutation occurs within the TK2 domain (Figure 1).
PDGFRA D842V mutation has been found in a distinct subset of GIST, typically from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance.
Atlas Image
Figure 1. Schematic representation of the most frequent activating mutations of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase in patients with gastrointestinal stromal tumors. Most common mutations are in exon 18, such as the D842V substitution that shows resistance to imatinib. Mutations in the juxtamembrane domain (exon 12; V561D most common) and in exon 14 tyrosine kinase 1 (TK1) domain (e.g., N659K) are less common. Abbreviations: JM, juxtamembrane; TK, tyrosine kinase. Adopted and modified from Pierott et al., 2011).
Entity name
Hematologic disorders with primary eosinophilia
Several chromosomal rearrangements generating fusion genes causing PDGFRA activation have been described in a variety of uncommon hematologic disorders that are often accompanied with a related condition called hypereosinophilic syndrome. These rearrangements activate PDGFRA by fusion to various partner genes: STRN (2p24) in the t(2;4)(p22;q12), FIP1L1 (interstitial 4q12 deletion), CDK5RAP2 (9q33) in the ins(9;4)(q33;q12q25), KIF5B (10p11) in the t(4;10)(q12;p11), ETV6 (12p13) in the t(4;12)(q12;p13), and BCR (22q11) in the t(4;22)(q12;q11). In each of these rearrangements, the breakpoints in PDGFRA partner genes are variable, but the breakpoints in PDGFRA invariably involve exon 12 encoding a portion of the juxtamembrane domain with autoinhibitory function (Baxter et al., 2002; Gotlib et al., 2008); the disruption of which activates the fusion protein (Figure 2).
The most investigated of these fusion genes is FIP1L1-PDGFRA that arise as a result of a cryptic interstitial deletion on chromosome 4q12. FIP1L1-PDGFRA fusion protein is involved in the pathogenesis of uncommon hematologic disorders with primary eosinophilia like chronic eosinophilic leukemia (CEL) hyperseosinophilic syndrome (HES) and systemic mastocytosis (SM). Similar to other fusion tyrosine kinases, FIP1L1-PDGFRA is a constitutively active tyrosine kinase that was shown to be sensitive to kinase inhibitors (Cools et al., 2003; Jain et al., 2013).
Atlas Image
Figure 2. The structure and mechanism of activation of PDGFRA fusions in hematological disorders. In the fusion oncogene, the partner gene always replaces the 5 part of exon 12 of PDGFRA creating an in frame fusion. As the 5 part of exon 12 of PDGFRA containing the inhibitory domain is truncated, its expression is controlled by the partner gene promoter resulting in constitutive activation of the PDGFRA kinase domain. NH2: N-terminal site; COOH: C-terminal site; TM: transmembrane domain; JM: juxtamembrane domain. Adopted and modified from Cools et al., 2003 and Gotlib et al., 2008).
Entity name
Lung adenocarcinoma
A t(4;12)(q12;q12) was found in a case of lung adenocarcinoma (Seo et al., 2012).
Hybrid gene


Atlas Image


Pubmed IDLast YearTitleAuthors
120239812002The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA.Baxter EJ et al
146995102004PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor.Chompret A et al
126603842003A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.Cools J et al
159283352005PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.Corless CL et al
224320872012Platelet-derived growth factors and their receptors in normal and malignant hematopoiesis.Demoulin JB et al
188432832008Five years since the discovery of FIP1L1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias.Gotlib J et al
200088512009Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors.Gramza AW et al
16975601990The human PDGF receptor alpha-subunit gene maps to chromosome 4 in close proximity to c-kit.Gronwald RG et al
125222572003PDGFRA activating mutations in gastrointestinal stromal tumors.Heinrich MC et al
239067122013Structural and functional properties of platelet-derived growth factor and stem cell factor receptors.Heldin CH et al
242039302013Imatinib therapy in a patient with suspected chronic neutrophilic leukemia and FIP1L1-PDGFRA rearrangement.Jain N et al
85864211995Structure, organization, and transcription units of the human alpha-platelet-derived growth factor receptor gene, PDGFRA.Kawagishi J et al
183123552008Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours.Lasota J et al
213646892011Targeted therapy in GIST: in silico modeling for prediction of resistance.Pierotti MA et al
229758052012The transcriptional landscape and mutational profile of lung adenocarcinoma.Seo JS et al

Other Information

Locus ID:

NCBI: 5156
MIM: 173490
HGNC: 8803
Ensembl: ENSG00000134853


dbSNP: 5156
ClinVar: 5156
TCGA: ENSG00000134853


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Calcium signaling pathwayKEGGko04020
Cytokine-cytokine receptor interactionKEGGko04060
Focal adhesionKEGGko04510
Gap junctionKEGGko04540
Regulation of actin cytoskeletonKEGGko04810
Prostate cancerKEGGko05215
MAPK signaling pathwayKEGGhsa04010
Calcium signaling pathwayKEGGhsa04020
Cytokine-cytokine receptor interactionKEGGhsa04060
Focal adhesionKEGGhsa04510
Gap junctionKEGGhsa04540
Regulation of actin cytoskeletonKEGGhsa04810
Pathways in cancerKEGGhsa05200
Prostate cancerKEGGhsa05215
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Central carbon metabolism in cancerKEGGhsa05230
Choline metabolism in cancerKEGGhsa05231
Central carbon metabolism in cancerKEGGko05230
Choline metabolism in cancerKEGGko05231
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA10804imatinibChemicalLabelAnnotation, VariantAnnotationambiguousPD30713339
PA151958383Gastrointestinal Stromal TumorsDiseaseMultilinkAnnotation, VariantAnnotationambiguousPD19248971, 30713339
PA166123046cessationDiseaseVariantAnnotationnot associatedPD30713339
PA443937Drug ToxicityDiseaseVariantAnnotationnot associatedPD30713339


Pubmed IDYearTitleCitations
201292512010Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.2371
125222572003PDGFRA activating mutations in gastrointestinal stromal tumors.502
126603842003A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.282
210928572010NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration.262
221377952011Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma.261
204793982010Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease.214
213978602011Twist1-induced invadopodia formation promotes tumor metastasis.196
223235972012Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response.182
159283352005PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.180
189554582008Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor.172


Adriana Zamecnikova ; Soad Al Bahar

PDGFRA (platelet-derived growth factor receptor, alpha polypeptide)

Atlas Genet Cytogenet Oncol Haematol. 2014-06-01

Online version: http://atlasgeneticsoncology.org/gene/143/pdgfra-(platelet-derived-growth-factor-receptor-alpha-polypeptide)