Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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PDGF Platelet-derived and vascular endothelial growth factors (PDGF, VEGF) family

SMART accession number:	SM00141
Description:	Platelet-derived growth factor is a potent activator for cells of mesenchymal origin. PDGF-A and PDGF-B form AA and BB homodimers and an AB heterodimer. Members of the VEGF family are homologues of PDGF.
Interpro abstract (IPR000072):	Platelet-derived growth factor (PDGF) [(PUBMED:2546599), (PUBMED:1425569)] is a potent mitogen for cells of mesenchymal origin, including smooth muscle cells and glial cells. In both mouse and human, the PDGF signalling network consists of four ligands, PDGFA-D, and two receptors, PDGFRalpha and PDGFRbeta. All PDGFs function as secreted, disulphide-linked homodimers, but only PDGFA and B can form functional heterodimers. PDGFRs also function as homo- and heterodimers. All known PDGFs have characteristic `PDGF domains', which include eight conserved cysteines that are involved in inter- and intramolecular bonds. Alternate splicing of the A chain transcript can give rise to two different forms that differ only in their C-terminal extremity. The transforming protein of Woolly monkey sarcoma virus (WMSV) (Simian sarcoma virus), encoded by the v-sis oncogene, is derived from the B chain of PDGF. PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiated mesenchyme and some progenitor populations. During later maturation stages, PDGF signalling has been implicated in tissue remodelling and cellular differentiation, and in inductive events involved in patterning and morphogenesis. In addition to driving mesenchymal proliferation, PDGFs have been shown to direct the migration, differentiation and function of a variety of specialised mesenchymal and migratory cell types, both during development and in the adult animal [(PUBMED:12952899)]. Other growth factors in this family include vascular endothelial growth factors B and C (VEGF-B, VEGF-C) [(PUBMED:8637916), (PUBMED:8617204)] which are active in angiogenesis and endothelial cell growth, and placenta growth factor (PlGF) which is also active in angiogenesis [(PUBMED:7681160)]. PDGF is structurally related to a number of other growth factors which also form disulphide-linked homo- or heterodimers.
GO component:	membrane (GO:0016020)
GO function:	growth factor activity (GO:0008083)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 510 PDGF domains in 510 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a PDGF domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with PDGF domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Takifugu rubripes

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Achen MG et al.
  • Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).
  • Proc Natl Acad Sci U S A. 1998; 95: 548-53
  • Display abstract

  • We have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.

  • Joukov V et al.
  • A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases.
  • EMBO J. 1996; 15: 290-98
  • Display abstract

  • Angiogenesis, the sprouting of new blood vessels from pre-existing ones, and the permeability of blood vessels are regulated by vascular endothelial growth factor (VEGF) via its two known receptors Flt1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2). The Flt4 receptor tyrosine kinase is related to the VEGF receptors, but does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. In this study, we have purified the Flt4 ligand, VEGF-C, and cloned its cDNA from human prostatic carcinoma cells. While VEGF-C is homologous to other members of the VEGF/platelet derived growth factor (PDGF) family, its C-terminal half contains extra cysteine-rich motifs characteristic of a protein component of silk produced by the larval salivary glands of the midge, Chironomus tentans. VEGF-C is proteolytically processed, binds Flt4, which we rename as VEGFR-3 and induces tyrosine autophosphorylation of VEGFR-3 and VEGFR-2. In addition, VEGF-C stimulated the migration of bovine capillary endothelial cells in collagen gel. VEGF-C is thus a novel regulator of endothelia, and its effects may extend beyond the lymphatic system, where Flt4 is expressed.

  • Meyer-Ingold W, Eichner W
  • Platelet-derived growth factor.
  • Cell Biol Int. 1995; 19: 389-98
  • Display abstract

  • Platelet-derived growth factor (PDGF) is a potent activator for cells of mesenchymal origin. Two different PDGF chains termed A and B encoded by different genes have been identified leading to three different PDGF isoforms, the AA and BB homodimers and the AB heterodimer. All three forms have been observed in vivo and possess biological activity in vitro with the AA homodimer being the poorest cellular mitogen. The availability of highly purified recombinant PDGF isoforms was the initial basis for comparative studies in order to specify the different spectra of activity of the various PDGF species. This review is particularly focused on AB heterodimer as from the standpoint of heterologous gene expression, this species is the one with the highest demands concerning expression and purification protocols. This explains the fact that, in comparison to PDGF-BB, only very limited data on the in vivo application of PDGF-AB are available so far.

  • Westermark B, Heldin CH
  • Platelet-derived growth factor. Structure, function and implications in normal and malignant cell growth.
  • Acta Oncol. 1993; 32: 101-5
  • Display abstract

  • Platelet-derived growth factor (PDGF) is a potent mitogen for a variety of cell types. PDGF is made up as dimers of A and B polypeptide chains which are combined to generate the three isoforms of PDGF (AA, AB, BB). These bind with different specificities and affinities to two types of cell surface receptors (the alpha-receptor and the beta-receptor), both being members of the protein tyrosine kinase family of growth factor receptors. A number of human tumor cell lines, particularly those established from glioma and sarcoma, have been shown to produce PDGF and express the cognate receptor type. In these instances, tumor cell growth may be enhanced by an autocrine receptor activation. In other tumor cell types, where PDGF is produced in the absence of receptor expression, the growth factor may act in a paracrine fashion. This view is supported by our recent finding that human melanoma cells that have been stably transfected with a PDGF B-chain cDNA, elicit a stroma response when transplanted to nude mice.

• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 15.42 map04060 Cytokine-cytokine receptor interaction 15.42 map04510 Focal adhesion 8.46 map05219 Bladder cancer 8.46 map04150 mTOR signaling pathway 8.46 map05211 Renal cell carcinoma 8.46 map05212 Pancreatic cancer 6.97 map04810 Regulation of actin cytoskeleton 6.97 map04540 Gap junction 6.97 map05215 Prostate cancer 6.97 map05218 Melanoma 3.73 map05214 Glioma 3.73 map04010 MAPK signaling pathway This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with PDGF domain which could be assigned to a KEGG orthologous group, and not all proteins containing PDGF domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of PDGF domains in PDB

  PDB code	Main view	Title
  1bj1		Vascular endothelial growth factor in complex with a neutralizing antibody
  1cz8		Vascular endothelial growth factor in complex with an affinity matured antibody
  1flt		Vegf in complex with domain 2 of the flt-1 receptor
  1fzv		The crystal structure of human placenta growth factor-1 (plgf-1), an angiogenic protein at 2.0a resolution
  1kat		Solution structure of a phage-derived peptide antagonist in complex with vascular endothelial growth factor
  1mjv		Disulfide deficient mutant of vascular endothelial growth factor a (c51a and c60a)
  1mkg		Disulfide deficient mutant of vascular endothelial growth factor a (c57a and c102a)
  1mkk		Disulfide deficient mutant of vascular endothelial growth factor a (c61a and c104a)
  1pdg		Crystal structure of human platelet-derived growth factor bb
  1qty		Vascular endothelial growth factor in complex with domain 2 of the flt-1 receptor
  1rv6		Crystal structure of plgf in complex with domain 2 of vegfr1
  1tzh		Crystal structure of the fab yads1 complexed with h-vegf
  1tzi		Crystal structure of the fab yads2 complexed with h-vegf
  1vpf		Structure of human vascular endothelial growth factor
  1vpp		Complex between vegf and a receptor blocking peptide
  1wq8		Crystal structure of vammin, a vegf-f from a snake venom
  1wq9		Crystal structure of vr-1, a vegf-f from a snake venom
  2c7w		Crystal structure of human vascular endothelial growth factor-b: identification of amino acids important for angiogeninc activity
  2fjg		Structure of the g6 fab, a phage derived fab fragment, in complex with vegf
  2fjh		Structure of the b20-4 fab, a phage derived fab fragment, in complex with vegf
  2gnn		Crystal structure of the orf virus nz2 variant of vegf-e
  2qr0		Structure of vegf complexed to a fab containing tyr and ser in the cdrs
  2vpf		Vascular endothelial growth factor refined to 1.93 angstroms resolution
  2vwe		Crystal structure of vascular endothelial growth factor-b in complex with a neutralizing antibody fab fragment
  3bdy		Dual specific bh1 fab in complex with vegf

• Links (links to other resources describing this domain)

• BLOCKS	PDGF
  PFAM	PDGF
  INTERPRO	IPR000072
  PROSITE	PDGF_DOMAIN

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