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99  structures 154  species 1  interaction 855  sequences 13  architectures

Family: PDGF (PF00341)

Summary: PDGF/VEGF domain

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This is the Wikipedia entry entitled "Platelet-derived growth factor". More...

Platelet-derived growth factor Edit Wikipedia article

"PDGF" redirects here. For the space hardware, see Power Data Grapple Fixture.
Platelet-derived growth factor (PDGF)
Identifiers
Symbol PDGF
Pfam PF00341
InterPro IPR000072
PROSITE PDOC00222
SCOP 1pdg
SUPERFAMILY 1pdg

In molecular biology, platelet-derived growth factor (PDGF) is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation (angiogenesis), the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled angiogenesis is a characteristic of cancer. In chemical terms, platelet-derived growth factor is a dimeric glycoprotein composed of two A (-AA) or two B (-BB) chains or a combination of the two (-AB).

PDGF[1][2] 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.

Though it is synthesized,[3] stored (in the alpha granules of platelets),[4] and released by platelets upon activation, it is produced by a plethora of cells including smooth muscle cells, activated macrophages, and endothelial cells[5]

Recombinant PDGF is used in medicine to help heal chronic ulcers and in orthopedic surgery and periodonistry to treat bone loss.

Types/Classification

There are five different isoforms of PDGF that activate cellular response through two different receptors. Known ligands include A (PDGFA), B (PDGFB), C (PDGFC), and D (PDGFD), and an AB heterodimer and receptors alpha (PDGFRA) and beta (PDGFRB). PDGF has few other members of the family, for example VEGF sub-family.

Mechanisms

The receptor for PDGF, PDGFR is classified as a receptor tyrosine kinase (RTK), a type of cell surface receptor. Two types of PDGFRs have been identified: alpha-type and beta-type PDGFRs.[6] The alpha type binds to PDGF-AA, PDGF-BB and PDGF-AB, whereas the beta type PDGFR binds with high affinity to PDGF-BB and PDGF-AB.[7] PDGF binds to PDGFRs ligand binding pocket located within the second and third immunoglobulin domains.[8] Upon activation by PDGF, these receptors dimerise, and are "switched on" by auto-phosphorylation of several sites on their cytosolic domains, which serve to mediate binding of cofactors and subsequently activate signal transduction, for example, through the PI3K pathway or through reactive oxygen species (ROS)-mediated activation of the STAT3 pathway.[9] Downstream effects of this include regulation of gene expression and the cell cycle. The role of PI3K has been investigated by several laboratories. Accumulating data suggests that, while this molecule is, in general, part of growth signaling complex, it plays a more profound role in controlling cell migration.[10] The different ligand isoforms have variable affinities for the receptor isoforms, and the receptor isoforms may variably form hetero- or homo- dimers. This leads to specificity of downstream signaling. It has been shown that the sis oncogene is derived from the PDGF B-chain gene. PDGF-BB is the highest-affinity ligand for the PDGFR-beta; PDGFR-beta is a key marker of hepatic stellate cell activation in the process of fibrogenesis.[citation needed]

Function

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.[11] Other growth factors in this family include vascular endothelial growth factors B and C (VEGF-B, VEGF-C)[12][13] which are active in angiogenesis and endothelial cell growth, and placenta growth factor (PlGF) which is also active in angiogenesis.[14]

PDGF plays a role in embryonic development, cell proliferation, cell migration, and angiogenesis.[15] Over-expression of PDGF has been linked to several diseases such as atherosclerosis, fibrotic disorders and malignancies. Synthesis occurs due to external stimuli such as thrombin, low oxygen tension, or other cytokines and growth factors.[16]

PDGF is a required element in cellular division for fibroblasts, a type of connective tissue cell that is especially prevalent in wound healing.[16] In essence, the PDGFs allow a cell to skip the G1 checkpoints in order to divide.[17] It has been shown that in monocytes-macrophages and fibroblasts, exogenously administered PDGF stimulates chemotaxis, proliferation, and gene expression and significantly augmented the influx of inflammatory cells and fibroblasts, accelerating extracellular matrix and collagen formation and thus reducing the time for the healing process to occur.[18]

In terms of osteogenic differentiation of mesenchymal stem cells, comparing PDGF to epidermal growth factor (EGF), which is also implicated in stimulating cell growth, proliferation, and differentiation,[19] MSCs were shown to have stronger osteogenic differentiation into bone-forming cells when stimulated by epidermal growth factor (EGF) versus PDGF. However, comparing the signaling pathways between them reveals that the PI3K pathway is exclusively activated by PDGF, with EGF having no effect. Chemically inhibiting the PI3K pathway in PDGF-stimulated cells negates the differential effect between the two growth factors, and actually gives PDGF an edge in osteogenic differentiation.[19] Wortmannin is a PI3K-specific inhibitor, and treatment of cells with Wortmannin in combination with PDGF resulted in enhanced osteoblast differentiation compared to just PDGF alone, as well as compared to EGF.[19] These results indicate that the addition of Wortmannin can significantly increase the response of cells into an osteogenic lineage in the presence of PDGF, and thus might reduce the need for higher concentrations of PDGF or other growth factors, making PDGF a more viable growth factor for osteogenic differentiation than other, more expensive growth factors currently used in the field such as BMP2.[20]

PDGF is also known to maintain proliferation of oligodendrocyte progenitor cells.[21][22] It has also been shown that fibroblast growth factor (FGF) activates a signaling pathway that positively regulates the PDGF receptors in oligodendrocyte progenitor cells.[23]

History

PDGF was one of the first growth factors characterized,[24] and has led to an understanding of the mechanism of many growth factor signaling pathways.[citation needed]


Medicine

Recombinant PDGF is used to help heal chronic ulcers and in orthopedic surgery and periodonistry to treat bone loss.[25]

Research

Like many other growth factors that have been linked to disease, PDGF and its receptors have provided a market for receptor antagonists to treat disease. Such antagonists include (but are not limited to) specific antibodies that target the molecule of interest, which act only in a neutralizing manner.[26]

The "c-Sis" oncogene is derived from PDGF.[22][27]

Age related downregulation of the PDGF receptor on islet beta cells has been demonstrated to prevent islet beta cell proliferation in both animal and human cells and its re-expression triggered beta cell proliferation and corrected glucose regulation via insulin secretion.[28][29]

A non-viral PDGF "bio patch" can regenerate missing or damaged bone by delivering DNA in a nano-sized particle directly into cells via genes. Repairing bone fractures, fixing craniofacial defects and improving dental implants are among potential uses. The patch employs a collagen platform seeded with particles containing the genes needed for producing bone. In experiments, it new bone fully covered skull wounds in test animals and stimulated growth in human bone marrow stromal cells.[30][31]

Family members

Human genes encoding proteins that belong to the platelet-derived growth factor family include:

See also

References

  1. ^ Hannink M, Donoghue DJ (1989). "Structure and function of platelet-derived growth factor (PDGF) and related proteins". Biochim. Biophys. Acta 989 (1): 1–10. doi:10.1016/0304-419x(89)90031-0. PMID 2546599. 
  2. ^ Heldin CH (1992). "Structural and functional studies on platelet-derived growth factor". EMBO J. 11 (12): 4251–4259. PMC 556997. PMID 1425569. 
  3. ^ Minarcik, John. "Global Path Course: Video". Retrieved 2011-06-27. 
  4. ^ "The Basic Biology of Platelet Growth Factors". Retrieved 2014-05-08. 
  5. ^ Kumar, Vinay (2010). Robbins and Coltran Pathologic Basis of Disease. China: Elsevier. pp. 88–89. ISBN 978-1-4160-3121-5. 
  6. ^ Matsui T, Heidaran M, Miki T, Popescu N, La Rochelle W, Kraus M, Pierce J, Aaronson S (1989). "Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes". Science 243 (4892): 800–4. doi:10.1126/science.2536956. PMID 2536956. 
  7. ^ Heidaran MA, Pierce JH, Yu JC, Lombardi D, Artrip JE, Fleming TP, Thomason A, Aaronson SA (25 October 1991). "Role of alpha beta receptor heterodimer formation in beta platelet-derived growth factor (PDGF) receptor activation by PDGF-AB". J. Biol. Chem. 266 (30): 20232–7. PMID 1657917. 
  8. ^ Heidaran MA, Pierce JH, Jensen RA, Matsui T, Aaronson SA (5 November 1990). "Chimeric alpha- and beta-platelet-derived growth factor (PDGF) receptors define three immunoglobulin-like domains of the alpha-PDGF receptor that determine PDGF-AA binding specificity". J. Biol. Chem. 265 (31): 18741–4. PMID 2172231. 
  9. ^ Blazevic T, Schwaiberger AV, Schreiner CE, Schachner D, Schaible AM, Grojer CS, Atanasov AG, Werz O, Dirsch VM, Heiss EH (December 2013). "12/15-Lipoxygenase Contributes to Platelet-derived Growth Factor-induced Activation of Signal Transducer and Activator of Transcription 3". J. Biol. Chem. 288 (49): 35592–603. doi:10.1074/jbc.M113.489013. PMC 3853304. PMID 24165129. 
  10. ^ Yu JC, Li W, Wang LM, Uren A, Pierce JH, Heidaran MA (1995). "Differential requirement of a motif within the carboxyl-terminal domain of alpha-platelet-derived growth factor (alpha PDGF) receptor for PDGF focus forming activity chemotaxis, or growth". J. Biol. Chem. 270 (13): 7033–6. doi:10.1074/jbc.270.13.7033. PMID 7706238. 
  11. ^ Hoch RV, Soriano P (2003). "Roles of PDGF in animal development". Development 130 (20): 4769–4784. doi:10.1242/dev.00721. PMID 12952899. 
  12. ^ Olofsson B, Pajusola K, Kaipainen A, von Euler G, Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U (1996). "Vascular endothelial growth factor B, a novel growth factor for endothelial cells". Proc. Natl. Acad. Sci. U.S.A. 93 (6): 2567–2581. doi:10.1073/pnas.93.6.2576. PMC 39839. PMID 8637916. 
  13. ^ Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (1996). "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. 15 (2): 290–298. PMC 449944. PMID 8617204. 
  14. ^ Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Alitalo K, Del Vecchio S, Lei KJ, Chou JY, Persico MG (1993). "Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14". Oncogene 8 (4): 925–931. PMID 7681160. 
  15. ^ "PDGF Pathways". Retrieved 2007-11-17. 
  16. ^ a b Alvarez RH, Kantarjian HM, Cortes JE (September 2006). "Biology of platelet-derived growth factor and its involvement in disease". Mayo Clin. Proc. 81 (9): 1241–57. doi:10.4065/81.9.1241. PMID 16970222. 
  17. ^ Song G, Ouyang G, Bao S (2005). "The activation of Akt/PKB signaling pathway and cell survival". J. Cell. Mol. Med. 9 (1): 59–71. doi:10.1111/j.1582-4934.2005.tb00337.x. PMID 15784165. 
  18. ^ Pierce GF, Mustoe TA, Altrock BW, Deuel TF, Thomason A (April 1991). "Role of platelet-derived growth factor in wound healing". J. Cell. Biochem. 45 (4): 319–26. doi:10.1002/jcb.240450403. PMID 2045423. 
  19. ^ a b c Kratchmarova I, Blagoev B, Haack-Sorensen M, Kassem M, Mann M (June 2005). "Mechanism of divergent growth factor effects in mesenchymal stem cell differentiation". Science 308 (5727): 1472–7. doi:10.1126/science.1107627. PMID 15933201. 
  20. ^ Hayashi, A. The New Standard of Care for Nonunions?. AAOS Now. 2009.
  21. ^ Barres BA, Hart IK, Coles HS, Burne JF, Voyvodic JT, Richardson WD, Raff MC (1992). "Cell Death and Control of Cell Survival in the Oligodendrocyte Lineage". Cell 70 (1): 31–46. doi:10.1016/0092-8674(92)90531-G. PMID 1623522. 
  22. ^ a b Proto-Oncogene Proteins c-sis at the US National Library of Medicine Medical Subject Headings (MeSH)
  23. ^ McKinnon RD, Matsui T, Dubois-Dalcq M, Aaronson SA (November 1990). "FGF modulates the PDGF-driven pathway of oligodendrocyte development". Neuron 5 (5): 603–14. doi:10.1016/0896-6273(90)90215-2. PMID 2171589. 
  24. ^ Paul D, Lipton A, Klinger I (1971). "Serum factor requirements of normal and simian virus 40-transformed 3T3 mouse fibroplasts". Proc Natl Acad Sci U S A. 68 (3): 645–52. doi:10.1073/pnas.68.3.645. PMC 389008. PMID 5276775. 
  25. ^ Friedlaender GE et al. The Role of Recombinant Human Platelet-derived Growth Factor-BB (rhPDGF-BB) in Orthopaedic Bone Repair and Regeneration Curr Pharm Des. 2013;19(19):3384-90. PMID 23432673. Quote: "Demonstration of the safety and efficacy of rhPDGF-BB in the healing of chronic foot ulcers in diabetic patients and regeneration of alveolar (jaw) bone lost due to chronic infection from periodontal disease has resulted in two FDA-approved products based on this molecule"
  26. ^ Shulman T, Sauer FG, Jackman RM, Chang CN, Landolfi NF (July 1997). "An antibody reactive with domain 4 of the platelet-derived growth factor beta receptor allows BB binding while inhibiting proliferation by impairing receptor dimerization". J. Biol. Chem. 272 (28): 17400–4. doi:10.1074/jbc.272.28.17400. PMID 9211881. 
  27. ^ McClintock JT, Chan IJ, Thaker SR, Katial A, Taub FE, Aotaki-Keen AE, Hjelmeland LM (1992). "Detection of c-sis proto-oncogene transcripts by direct enzyme-labeled cDNA probes and in situ hybridization". In Vitro Cell Dev Biol 28A (2): 102–8. doi:10.1007/BF02631013. PMID 1537750. 
  28. ^ "Researchers make older beta cells act young again". Eurekalert.org. 2011-10-12. Retrieved 2013-12-28. 
  29. ^ "New Stanford molecular target for diabetes treatment discovered - Office of Communications & Public Affairs - Stanford University School of Medicine". Med.stanford.edu. 2011-10-12. Retrieved 2013-12-28. 
  30. ^ "Bio patch can regrow bone for dental implants and craniofacial defects". KurzweilAI. 2013-11-12. doi:10.1016/j.biomaterials.2013.10.021. Retrieved 2013-12-28. 
  31. ^ Elangovan S, D'Mello SR, Hong L, Ross RD, Allamargot C, Dawson DV, Stanford CM, Johnson GK, Sumner DR, Salem AK (2014). "The enhancement of bone regeneration by gene activated matrix encoding for platelet derived growth factor". Biomaterials 35 (2): 737–747. doi:10.1016/j.biomaterials.2013.10.021. PMC 3855224. PMID 24161167. 

External links

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

PDGF/VEGF domain Provide feedback

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry 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.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Cystine-knot (CL0079), which has the following description:

The cytokine families in this clan have the cystine-knot fold. In this 6 cysteines form three disulphide bridges that are interlinked.

The clan contains the following 9 members:

Coagulin Cys_knot DAN Hormone_6 NGF Noggin PDGF Sclerostin TGF_beta

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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(57)
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(797)
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  Seed
(57)
Full
(855)
Representative proteomes NCBI
(797)
Meta
(0)
RP15
(40)
RP35
(65)
RP55
(165)
RP75
(329)
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  Seed
(57)
Full
(855)
Representative proteomes NCBI
(797)
Meta
(0)
RP15
(40)
RP35
(65)
RP55
(165)
RP75
(329)
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MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Domain
Author: Finn RD, Bateman A
Number in seed: 57
Number in full: 855
Average length of the domain: 80.20 aa
Average identity of full alignment: 36 %
Average coverage of the sequence by the domain: 33.29 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.8 20.8
Trusted cut-off 22.8 21.5
Noise cut-off 19.4 19.4
Model length: 82
Family (HMM) version: 12
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Species distribution

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Interactions

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PDGF

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the PDGF domain has been found. There are 99 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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