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

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

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

Identity

HGNC
LOCATION
22q13.1
LOCUSID
ALIAS
IBGC5,PDGF-2,PDGF2,SIS,SSV,c-sis
FUSION GENES

DNA/RNA

Atlas Image

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

Atlas Image

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. , 
  • Giant cell fibrosarcoma (GCF) (juvenile form of DP). , 
  • 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).
  • Atlas Image
    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
  • Atlas Image
    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

    Atlas Image

    Bibliography

    Pubmed IDLast YearTitleAuthors
    22380871990Brittle bones--fragile molecules: disorders of collagen gene structure and expression.Byers PH et al
    90165321997The human type I collagen mutation database.Dalgleish R et al
    85997391996Soft tissue sarcomas in dermatology.Fish FS et al
    97719751998Transforming 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
    97397611998Signal transduction via platelet-derived growth factor receptors.Heldin CH et al
    95917281998Fibrosarcomatous ("high-grade") dermatofibrosarcoma protuberans: clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance.Mentzel T et al
    97905081998COL1A1-PDGFB fusion in a ring chromosome 4 found in a dermatofibrosarcoma protuberans.Navarro M et al
    111702902001Supernumerary 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
    97390231998Various 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
    89787651996Translocation, t(17;22)(q22;q13), in dermatofibrosarcoma protuberans: a new tumor-associated chromosome rearrangement.Pedeutour F et al
    104469871999The 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
    114207092001Structural 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
    89881771997Deregulation 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
    105656811999Detection 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 IDTranscript IDUniprot
    ENSG00000100311ENST00000331163P01127
    ENSG00000100311ENST00000331163A0A384NYY3
    ENSG00000100311ENST00000381551P01127
    ENSG00000100311ENST00000440375A9UJN9
    ENSG00000100311ENST00000455790A9UJP0

    Expression (GTEx)

    0
    5
    10
    15
    20
    25
    30
    35
    40
    45
    50

    Pathways

    PathwaySourceExternal ID
    MAPK signaling pathwayKEGGko04010
    Cytokine-cytokine receptor interactionKEGGko04060
    Focal adhesionKEGGko04510
    Gap junctionKEGGko04540
    Regulation of actin cytoskeletonKEGGko04810
    Renal cell carcinomaKEGGko05211
    GliomaKEGGko05214
    Prostate cancerKEGGko05215
    MelanomaKEGGko05218
    MAPK signaling pathwayKEGGhsa04010
    Cytokine-cytokine receptor interactionKEGGhsa04060
    Focal adhesionKEGGhsa04510
    Gap junctionKEGGhsa04540
    Regulation of actin cytoskeletonKEGGhsa04810
    Pathways in cancerKEGGhsa05200
    Renal cell carcinomaKEGGhsa05211
    GliomaKEGGhsa05214
    Prostate cancerKEGGhsa05215
    MelanomaKEGGhsa05218
    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
    Choline metabolism in cancerKEGGhsa05231
    Choline metabolism in cancerKEGGko05231
    DiseaseREACTOMER-HSA-1643685
    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
    HemostasisREACTOMER-HSA-109582
    Platelet activation, signaling and aggregationREACTOMER-HSA-76002
    Response to elevated platelet cytosolic Ca2+REACTOMER-HSA-76005
    Platelet degranulationREACTOMER-HSA-114608
    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
    VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
    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
    Extracellular matrix organizationREACTOMER-HSA-1474244
    Non-integrin membrane-ECM interactionsREACTOMER-HSA-3000171
    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
    Fluid shear stress and atherosclerosisKEGGko05418
    Fluid shear stress and atherosclerosisKEGGhsa05418

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    172928262007High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene.187
    207396602010Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization.102
    200196692010Molecular basis for antagonism between PDGF and the TGFbeta family of signalling pathways by control of miR-24 expression.90
    199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
    214299372011Mesenchymal stem cell migration is regulated by fibronectin through α5β1-integrin-mediated activation of PDGFR-β and potentiation of growth factor signals.76
    194980032009Prognostic significance of stromal platelet-derived growth factor beta-receptor expression in human breast cancer.75
    239130032013Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice.70
    216182762011PDGF in bone formation and regeneration: new insights into a novel mechanism involving MSCs.59
    158269412005WAVE3-mediated cell migration and lamellipodia formation are regulated downstream of phosphatidylinositol 3-kinase.51
    229083242012Endothelial 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-platelet-derived-growth-factor-beta-polypeptide-(simian-sarcoma-viral-(v-sis)-oncogene-homolog)