PDGFB platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)

2001-02-01 Marie-Pierre Simon , Georges Maire , Florence Pedeutour Affiliation

Laboratoire de Genetique, Hopital de lArchet, 151 route de Saint Antoine de Ginestiere BP 3079, 06202 Nice Cedex 3, France

Identity

HGNC

PDGFB

LOCATION

22q13.1

LOCUSID

5155

ALIAS

IBGC5,PDGF-2,PDGF2,SIS,SSV,c-sis

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

The PDGFB gene encodes the human platelet-derived growth factor (PDGF) B chain precursor and is the cellular homologue of the v-sis oncogene. PDGFB gene is 22 kb in size and is composed of 7 exons. The exon 7 and most part of the exon 1 are non coding sequences (white boxes).

Transcription

The PDGFB chain precursor is usually translated from a 3.5 kb transcript. The first exon contains the sequence for the signal peptide preceeded by a 1 kb-long untranslated sequence with potent translation inhibitory activity. A 2.6 kb mRNA which initiates at an alternative exon 1, exon 1A, was described in the human choriocarcinoma cell line JEG-3. It initiates an open reading frame that is continuous with the code for the PDGF B chain precursor but lacks the code for the signal peptide.

Proteins

Description

The PDGFB chains are synthesised as 240 amino acids precursors molecules containing amino and carboxy-terminal propeptides, which are removed by site-specific endopeptidases. Two PDGFB precursor chains associate in dimers to form the mature PDGFBB after proteolysis.

Expression

First isolated from human platelets, the PDGFBB is synthesized by a variety of different cell lineages.

Localisation

Secreted in the extra-cellular medium

Function

The homodimer PDGFBB is a potent growth factor that acts as a mitogen and chemo-attractant for a variety of cells from mesenchymal origin. It has various roles in embryonic development, tissue regeneration, osteogenesis, fibrosis, atherosclerosis, and neoplasia.

Homology

Member of the PDGF/VEGF family

Implicated in

Entity name

Dermatofibrosarcoma Protuberans (DP), also called Darier Ferrand tumour or Darier-Hoffmann tumour.

Entity name

Giant cell fibrosarcoma (GCF) (juvenile form of DP).

Entity name

Bednar tumour (pigmented variant of DP)

Disease

Infiltrative skin tumours of intermediate malignancy

Prognosis

The prognosis is usually favourable. These tumours are locally aggressive and highly recurrent, but metastases or tumour-related deaths are extremely rare.

Cytogenetics

Dermatofibrosarcoma Protuberans, Giant Cell fibrosarcoma and Bednar tumours present specific cytogenetic features such as reciprocal translocations t(17;22)(q22;q13.1) ( Fig A) or, more often, supernumerary ring chromosomes derived from t(17;22) (B). As shown by FISH analysis, the ring chromosomes contain chromosome 22 centromere and low-level amplification of 22cen-q13.1 and 17q22-qter sequences. To note, in most cases, the derivative chromosome 17 is not present. In contrast, several copies of the derivative chromosome 22 are generally observed.in addition to two apparently normal chromosomes 17

Hybrid gene

Both rings and der(22) translocated chromosomes present a same molecular rearrangement that fuses the collagen type I alpha 1(COL1A1) and the platelet-derived growth factor B chain (PDGFB) genes (C).

In all DP and GCF cases studied, the t(17;22)translocation results in chimerical COL1A1/PDGFB mRNA production, in which the PDGFB exon 1 is deleted and replaced by a variable segment of COL1A1 mRNA sequence. In the 32 cases tested the fusion mRNA was an in-frame fusion of one of the COL1A1 exons (varying from exon 7 to exon 47) to PDGFB exon 2 (D).

Fusion protein

COL1A1 and PDGFB are both encoded as pro-peptides, which are processed by proteolytic cleavage at N and C-terminus, to give mature proteins. Sequences analyses of the chimerical COL1A1/PDGFB fusion transcripts showed that the COL1A1/PDGFB putative proteins displayed a pro-peptide structure, which preserved the N-terminus COL1A1 pro-peptide containing the signal peptide and the N and C-terminus PDGFB maturation cleavage sites.

The functional and structural properties of the COL1A1/PDGFB fusion protein were characterized by generating stable fibroblastic cell lines that expressed tumour-derived COL1A1/PDGFB chimerical genes. The diagram herein given presents the COL1A1/PDGFB chimerical protein encoded by the T94796 tumour-derived chimerical COL1A1/PDGFB cDNA sequence

A chimerical COL1A1/PDGFB cDNA sequence fusing COL1A1 exon 29 to PDGFB exon 2 was isolated from the DP T94796 tumour and stably transfected in the Chinese hamster lung fibroblastic cell line PS200 (E).

The T94796 COL1A1/PDGFB chimerical protein sequence retained the COL1A1 N-terminus processing site encoded by the COL1A1 exon 6 and the N and C-terminus PDGFB processing sites encoded by the PDGFB exons 3 and 6 respectively (F).

Mutagenesis experiments and immunodetection with anti-PDGFBB and specific anti-COL1A1/PDGFB antibodies showed that COL1A1/PDGFB expressing cells produced 116 kD chimerical COL1A1/PDGFB precursors chains, which formed dimers and were processed to give active 30 kD PDGFB-like dimers (G).

Oncogenesis

Transfected cells lines expressing the chimerical T94796-COL1A1/PDGFB proteins became independent upon growth factors, including PDGFB, and induced tumours formation in nude mice. In addition, it was shown that the COL1A1/PDGFB stable clones cells contained activated PDGF b-receptors and that the conditioned media from COL1A1/PDGFB transfected cells were able to stimulate fibroblastic cells growth. Anti-PDGFBB antibodies neutralized this effect.

These results strongly suggest that the COL1A1/PDGFB chimerical gene expression associated with DP, contributes to tumour formation through ectopic production of mature PDGFB and the formation of an autocrine loop.

Breakpoints

Bibliography

Pubmed ID	Last Year	Title	Authors
2238087	1990	Brittle bones--fragile molecules: disorders of collagen gene structure and expression.	Byers PH et al
9016532	1997	The human type I collagen mutation database.	Dalgleish R et al
8599739	1996	Soft tissue sarcomas in dermatology.	Fish FS et al
9771975	1998	Transforming activity of the chimeric sequence formed by the fusion of collagen gene COL1A1 and the platelet derived growth factor b-chain gene in dermatofibrosarcoma protuberans.	Greco A et al
9739761	1998	Signal transduction via platelet-derived growth factor receptors.	Heldin CH et al
9591728	1998	Fibrosarcomatous ("high-grade") dermatofibrosarcoma protuberans: clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance.	Mentzel T et al
9790508	1998	COL1A1-PDGFB fusion in a ring chromosome 4 found in a dermatofibrosarcoma protuberans.	Navarro M et al
11170290	2001	Supernumerary ring chromosome in a Bednar tumor (pigmented dermatofibrosarcoma protuberans) is composed of interspersed sequences from chromosomes 17 and 22: a fluorescence in situ hybridization and comparative genomic hybridization analysis.	Nishio J et al
9739023	1998	Various regions within the alpha-helical domain of the COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant-cell fibroblastomas.	O'Brien KP et al
8978765	1996	Translocation, t(17;22)(q22;q13), in dermatofibrosarcoma protuberans: a new tumor-associated chromosome rearrangement.	Pedeutour F et al
10446987	1999	The dermatofibrosarcoma protuberans-associated collagen type Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB.	Shimizu A et al
11420709	2001	Structural and functional analysis of a chimeric protein COL1A1-PDGFB generated by the translocation t(17;22)(q22;q13.1) in Dermatofibrosarcoma protuberans (DP).	Simon MP et al
8988177	1997	Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma.	Simon MP et al
10565681	1999	Detection of COL1A1-PDGFB fusion transcripts in dermatofibrosarcoma protuberans by reverse transcription-polymerase chain reaction using archival formalin-fixed, paraffin-embedded tissues.	Wang J et al

Other Information

Locus ID:

NCBI: 5155
MIM: 190040
HGNC: 8800
Ensembl: ENSG00000100311

Variants:

dbSNP: 5155
ClinVar: 5155
TCGA: ENSG00000100311
COSMIC: PDGFB

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000100311	ENST00000331163	P01127
ENSG00000100311	ENST00000331163	A0A384NYY3
ENSG00000100311	ENST00000381551	P01127
ENSG00000100311	ENST00000440375	A9UJN9
ENSG00000100311	ENST00000455790	A9UJP0

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
MAPK signaling pathway	KEGG	ko04010
Cytokine-cytokine receptor interaction	KEGG	ko04060
Focal adhesion	KEGG	ko04510
Gap junction	KEGG	ko04540
Regulation of actin cytoskeleton	KEGG	ko04810
Renal cell carcinoma	KEGG	ko05211
Glioma	KEGG	ko05214
Prostate cancer	KEGG	ko05215
Melanoma	KEGG	ko05218
MAPK signaling pathway	KEGG	hsa04010
Cytokine-cytokine receptor interaction	KEGG	hsa04060
Focal adhesion	KEGG	hsa04510
Gap junction	KEGG	hsa04540
Regulation of actin cytoskeleton	KEGG	hsa04810
Pathways in cancer	KEGG	hsa05200
Renal cell carcinoma	KEGG	hsa05211
Glioma	KEGG	hsa05214
Prostate cancer	KEGG	hsa05215
Melanoma	KEGG	hsa05218
HTLV-I infection	KEGG	ko05166
HTLV-I infection	KEGG	hsa05166
PI3K-Akt signaling pathway	KEGG	hsa04151
PI3K-Akt signaling pathway	KEGG	ko04151
MicroRNAs in cancer	KEGG	hsa05206
MicroRNAs in cancer	KEGG	ko05206
Ras signaling pathway	KEGG	hsa04014
Rap1 signaling pathway	KEGG	hsa04015
Rap1 signaling pathway	KEGG	ko04015
Choline metabolism in cancer	KEGG	hsa05231
Choline metabolism in cancer	KEGG	ko05231
Disease	REACTOME	R-HSA-1643685
Diseases of signal transduction	REACTOME	R-HSA-5663202
PI3K/AKT Signaling in Cancer	REACTOME	R-HSA-2219528
Constitutive Signaling by Aberrant PI3K in Cancer	REACTOME	R-HSA-2219530
Immune System	REACTOME	R-HSA-168256
Adaptive Immune System	REACTOME	R-HSA-1280218
Signaling by the B Cell Receptor (BCR)	REACTOME	R-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)	REACTOME	R-HSA-1168372
PIP3 activates AKT signaling	REACTOME	R-HSA-1257604
Negative regulation of the PI3K/AKT network	REACTOME	R-HSA-199418
Innate Immune System	REACTOME	R-HSA-168249
DAP12 interactions	REACTOME	R-HSA-2172127
DAP12 signaling	REACTOME	R-HSA-2424491
RAF/MAP kinase cascade	REACTOME	R-HSA-5673001
Fc epsilon receptor (FCERI) signaling	REACTOME	R-HSA-2454202
FCERI mediated MAPK activation	REACTOME	R-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilization	REACTOME	R-HSA-2730905
Cytokine Signaling in Immune system	REACTOME	R-HSA-1280215
Signaling by Interleukins	REACTOME	R-HSA-449147
Interleukin-2 signaling	REACTOME	R-HSA-451927
Interleukin receptor SHC signaling	REACTOME	R-HSA-912526
Interleukin-3, 5 and GM-CSF signaling	REACTOME	R-HSA-512988
Hemostasis	REACTOME	R-HSA-109582
Platelet activation, signaling and aggregation	REACTOME	R-HSA-76002
Response to elevated platelet cytosolic Ca2+	REACTOME	R-HSA-76005
Platelet degranulation	REACTOME	R-HSA-114608
Signal Transduction	REACTOME	R-HSA-162582
Signaling by EGFR	REACTOME	R-HSA-177929
GRB2 events in EGFR signaling	REACTOME	R-HSA-179812
SHC1 events in EGFR signaling	REACTOME	R-HSA-180336
GAB1 signalosome	REACTOME	R-HSA-180292
Signaling by Insulin receptor	REACTOME	R-HSA-74752
Insulin receptor signalling cascade	REACTOME	R-HSA-74751
IRS-mediated signalling	REACTOME	R-HSA-112399
SOS-mediated signalling	REACTOME	R-HSA-112412
Signalling by NGF	REACTOME	R-HSA-166520
NGF signalling via TRKA from the plasma membrane	REACTOME	R-HSA-187037
Signalling to ERKs	REACTOME	R-HSA-187687
Signalling to RAS	REACTOME	R-HSA-167044
Signalling to p38 via RIT and RIN	REACTOME	R-HSA-187706
Prolonged ERK activation events	REACTOME	R-HSA-169893
Frs2-mediated activation	REACTOME	R-HSA-170968
ARMS-mediated activation	REACTOME	R-HSA-170984
PI3K/AKT activation	REACTOME	R-HSA-198203
Signaling by PDGF	REACTOME	R-HSA-186797
Downstream signal transduction	REACTOME	R-HSA-186763
Signaling by VEGF	REACTOME	R-HSA-194138
VEGFA-VEGFR2 Pathway	REACTOME	R-HSA-4420097
VEGFR2 mediated cell proliferation	REACTOME	R-HSA-5218921
Signaling by SCF-KIT	REACTOME	R-HSA-1433557
MAPK family signaling cascades	REACTOME	R-HSA-5683057
MAPK1/MAPK3 signaling	REACTOME	R-HSA-5684996
Signaling by GPCR	REACTOME	R-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPK	REACTOME	R-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	REACTOME	R-HSA-2404192
IGF1R signaling cascade	REACTOME	R-HSA-2428924
IRS-related events triggered by IGF1R	REACTOME	R-HSA-2428928
Signaling by Leptin	REACTOME	R-HSA-2586552
Extracellular matrix organization	REACTOME	R-HSA-1474244
Non-integrin membrane-ECM interactions	REACTOME	R-HSA-3000171
Developmental Biology	REACTOME	R-HSA-1266738
Axon guidance	REACTOME	R-HSA-422475
NCAM signaling for neurite out-growth	REACTOME	R-HSA-375165
Phospholipase D signaling pathway	KEGG	ko04072
Phospholipase D signaling pathway	KEGG	hsa04072
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	REACTOME	R-HSA-6811558
EGFR tyrosine kinase inhibitor resistance	KEGG	ko01521
EGFR tyrosine kinase inhibitor resistance	KEGG	hsa01521
RET signaling	REACTOME	R-HSA-8853659
Fluid shear stress and atherosclerosis	KEGG	ko05418
Fluid shear stress and atherosclerosis	KEGG	hsa05418

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
17292826	2007	High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene.	187
20739660	2010	Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization.	102
20019669	2010	Molecular basis for antagonism between PDGF and the TGFbeta family of signalling pathways by control of miR-24 expression.	90
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85
21429937	2011	Mesenchymal stem cell migration is regulated by fibronectin through α5β1-integrin-mediated activation of PDGFR-β and potentiation of growth factor signals.	76
19498003	2009	Prognostic significance of stromal platelet-derived growth factor beta-receptor expression in human breast cancer.	75
23913003	2013	Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice.	70
21618276	2011	PDGF in bone formation and regeneration: new insights into a novel mechanism involving MSCs.	59
15826941	2005	WAVE3-mediated cell migration and lamellipodia formation are regulated downstream of phosphatidylinositol 3-kinase.	51
22908324	2012	Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression.	51

Citation

Marie-Pierre Simon ; Georges Maire ; Florence Pedeutour

PDGFB platelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)

Atlas Genet Cytogenet Oncol Haematol. 2001-02-01

Online version: http://atlasgeneticsoncology.org/gene/155/pdgfb