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FLASH GENE

Symbol

PDGFRA

contributors: mct/pgu - updated : 30-11-2017

HGNC name	platelet-derived growth factor receptor, alpha polypeptide
HGNC id	8803

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	HES1 idiopathic hypereosinophilic syndrome 1 TAPVR1 total anomalous pulmonary venous return, 1
Location	4q12      Physical location : 55.095.263 - 55.164.411
Synonym name	FIP1L1/PDGFRA fusion protein
	rearranged-in-hypereosinophilia-platelet derived growth factor receptor
	alpha fusion protein
	CD140 antigen-like family member A
	alpha-type platelet-derived growth factor receptor
	PDGFRA/BCR fusion
Synonym symbol(s)	CD140A, PDGFR2, MGC74795, RHEPDGFRA
EC.number	2.7.10.1

DNA

TYPE	like-sequence
STRUCTURE	69.15 kb     23 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor
text structure	controlled by an ATTA-sequence-containing element located near the transcription initiation site, which is bound by a transcriptional complex that includes PBX and PRX homeobox transcription factors
	translation start codon located in exon 2
	putative E2F-binding sequences in the P1 promoter

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	alternate exon1 (exon 1 and exon 1 beta)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_006206 23 - 6574 NP_006197 - 1089 - 2017 28734947 NM_001347827 - - 3077 NP_001334756 - 807 - 2017 28734947 exon 1 beta regulated by E2F1 through an E2F1-responsive site located at position + 1086/+ 1093 downstream of the transcriptional initiation site of the type I transcript NM_001347828 - - 6668 NP_001334757 - 1114 - 2017 28734947 NM_001347829 - - 6625 NP_001334758 - 1089 - 2017 28734947 NM_001347830 - - 6802 NP_001334759 - 1102 - 2017 28734947

EXPRESSION

Type

widely

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic spleen       highly Cardiovascular heart       highly Endocrine pancreas       highly Homo sapiens Hearing/Equilibrium ear       predominantly Nervous brain       highly   spinal cord         Reproductive male system prostate     moderately Skin/Tegument skin         Homo sapiens Fetal Urinary kidney       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective interstitial dermis     Homo sapiens Fetal Muscular striatum skeletal     Nervous central

cells

System Cell Pubmed Species Stage Rna symbol Endocrine islet cell (alpha,beta...) Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

growth/childhood

Text	PDGFRB levels were markedly reduced in islet beta-cells at 6 weeks and 6 months of age, compared to neonatal islets

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	receptor tyrosine kinase, class III, with five extracellular Ig-like motifs
	a transmembrane segment (1TM)
	a cytoplasmic split tyrosine kinase domain

mono polymer

homomer , heteromer , dimer

HOMOLOGY

Homologene

FAMILY	immunoglobulin superfamily
	protein kinase superfamily
	Tyr protein kinase family
	CSF-1/PDGF receptor subfamily

CATEGORY

signaling cytokine growth factor , receptor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm
	intracellular,nucleus

basic FUNCTION	growth arrest specific gene (gas), subunit, receptor tyrosine kinase, class III, binding both PDGFA and PDGFB and having a tyrosine-protein kinase activity
	implicated in several cellular processes such as cell proliferation, normal development, and tumorigenesis
	is required for medial nasal processes (MNP) development by maintaining the migration of progenitor neural crest cells (NCCs) and the proliferation of MNP cells
	is a novel regulator of MNP development, elucidating the roles of its downstream signaling pathways at cellular and molecular levels
	is crucial for controlling the production of oligodendrocytes (OLs) for myelination
	PDGFRA targets progenitor cell plasticity as a profibrotic mechanism
	PDGFRA signaling promotes lung alveolar septation by regulating fibroblast activation and matrix fibroblast differentiation, whereas myofibroblast differentiation was largely PDGFRA independent
	PDGFRA may be a relevant target to regulate connective tissue remodeling
	importance of balancing stromal versus adipogenic cell expansion during white adipose tissue development, with PDGFRA activity coordinating this crucial process in the embryo
	constitutive activation of PDGFRA leads to expansion of cartilage underlying the coronal sutures, which contribute to suture closure through endochondral ossification, in a process regulated in part by PI3K/AKT signaling

CELLULAR PROCESS	cell life, proliferation/growth

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

receptor tyrosine kinase pathway

a component

homodimerizing and heterodimerizing with PDGFRB

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP

protein	GLI (target gene of GLI)
	binding ZNF148(disrupted in prmitive neuroectodermal tumors and ependymomas)
	interacting with NRP1
	regulates pancreatic beta-cell EZH2 expression and proliferation
	JAK2 is a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in chronic eosinophilic leukemia (CEL)
	PHF14 acts as a negative regulator of PDGFRA expression in mesenchymal cells
	HOXC6 play an important role in several cellular events through the regulation of its functional biological targets such as BMP7, FGFR2, and PDGFRA
	FREM1 binds to PDGFC and this interaction regulates signalling downstream of PDGFRA
	NKX2-2 can directly bind to the promoter of platelet-derived growth factor receptor alpha (PDGFRA) and repress its gene expression
	sulfatide accumulation significantly impacts the formation of oligodendrocytes (OLs) via deregulation of PDGFRA function
	PDGFRA signaling up-regulates MTOR signaling and ribosome biogenesis pathways and perturbs the expression of a network of epigenetically imprinted genes that have been implicated in cell growth and tissue homeostasis
	PDGFA/PDGFRA signalling as a tissue-autonomous regulator of contact inhibition of locomotion (CIL) by controlling N-cadherin upregulation during epithelial-to-mesenchymal transition (EMT)
	is a cell-surface receptor tyrosine kinase for platelet-derived growth factors

cell & other

REGULATION

Other

regulated by E2F1

ASSOCIATED DISORDERS

corresponding disease(s)

TAPVR1 , HES1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion       with BCR in t (4;22) (q12;q11) in atypical chronic myeloid leukemia tumoral somatic mutation     gain of function in gastrointestinal stromal tumors tumoral     --over   in basal cell carcinoma tumoral fusion deletion     acquired 4q12 deletion resulting in FIP1L1/PDGFRA fusion gene in about half of the cases of idiopathic hypereosinophilic syndrome tumoral somatic mutation       in synovial sarcomas tumoral   amplification     in intimal sarcoma, which should be considered as a molecular hallmark of this entity tumoral   amplification     coamplification of PDGFRA or KDR with KIT may be clinically useful novel molecular markers in medulloblastomas and primitive neuroectodermal tumors tumoral   amplification     rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas constitutional     --over   dysregulated PDGFRA expression could cause orofacial cleft, spina bifida and omphalocele

Susceptibility

to neural tube defects to primitive neurectodermal tumours and ependymomas to variation of corneal curvature to isolated cleft palate (CP)

Variant & Polymorphism SNP	haplotype H2 delta in the promoter associated with primitive neurectodermal tumours and ependymomas
	six single nucleotide polymorphisms (SNPs)associated with variation of corneal curvature
	single base-pair substitutions in the PDGFRA in patients with CP (8.8p100)

Candidate gene
Marker	PDGFRA immunopositivity reflects PDGFRA mutational status and is associated with a favorable outcome in gastrointestinal stromal tumors
	PDGFRA may serve as a candidate prognostic marker for HCC (hepatocellular carcinoma)
Therapy target
	System Type Disorder Pubmed cancer hemopathy   may represent a potential therapeutic target in thymic tumours cancer digestive liver targeted inhibition of PDGFRA is a rational strategy for prevention and therapy of hepatocellular carcinoma cancer digestive liver PDGFRA may serve as a novel therapeutic target for HCC cancer reproductive breast PDGFRA, HSD17B4 and HMGB2 are potential therapeutic targets in polycystic ovarian syndrome and breast cancer

ANIMAL & CELL MODELS

	deletion of Pdgfra at different embryonic days (between E7.5 and E10.5) resulted in orofacial cleft, spina bifida, rib cage deformities, and omphalocele
	increased Pdgfra activity causes adipose tissue fibrosis in adult mice