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Platelet-derived growth factor

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Platelet-derived growth factor (PDGF)
Identifiers
SymbolPDGF
PfamPF00341
InterProIPR000072
PROSITEPDOC00222
SCOP21pdg / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1mkkA:52-130 1mkgA:52-130 1cz8V:52-130

1vpfD:52-130 1bj1V:52-130 2vpfE:52-130 1tziV:52-130 1vppV:52-130 1mjvB:52-130 1fltV:52-130 Template:PD B3V:52-130 1tzhW:52-130 1qtyR:52-130 1rv6V:52-130 1fzvB:52-130

1pdgA:97-180 1owuA:101-184

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 and released by platelets upon activation, it is produced by a plethora of cells including smooth muscle cells, activated macrophages, and endothelial cells[4]

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.[5] 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.[6] PDGF binds to PDGFRs ligand binding pocket located within the second and third immunoglobulin domains.[7] 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.[8] 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.[9] 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 cis 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.[10] Other growth factors in this family include vascular endothelial growth factors B and C (VEGF-B, VEGF-C)[11][12] which are active in angiogenesis and endothelial cell growth, and placenta growth factor (PlGF) which is also active in angiogenesis.[13]

PDGF plays a role in embryonic development, cell proliferation, cell migration, and angiogenesis.[14] 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.[15]

PDGF is a required element in cellular division for fibroblasts, a type of connective tissue cell that is especially prevalent in wound healing.[15] In essence, the PDGFs allow a cell to skip the G1 checkpoints in order to divide.[16] 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.[17]

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,[18] 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.[18] 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.[18] 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.[19]

PDGF is also known to maintain proliferation of oligodendrocyte progenitor cells.[20][21] It has also been shown that fibroblast growth factor (FGF) activates a signaling pathway that positively regulates the PDGF receptors in oligodendrocyte progenitor cells.[22]

History

PDGF was one of the first growth factors characterized,[23] and has led to an understanding of the mechanism of many growth factor signaling pathways.[citation needed]

Clinical significance

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.[24]

The "c-Sis" oncogene is derived from PDGF.[21][25]

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.[26][27]

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. 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. ^ Kumar, Vinay (2010). Robbins and Coltran Pathologic Basis of Disease. China: Elsevier. pp. 88–89. ISBN 978-1-4160-3121-5.
  5. ^ Matsui T, Heidaran M, Miki T; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  6. ^ Heidaran MA, Pierce JH, Yu JC; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  7. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Blazevic, T.; Schwaiberger, A. V.; Schreiner, C. E.; Schachner, D.; Schaible, A. M.; Grojer, C. S.; Atanasov, A. G.; Werz, O.; Dirsch, V. M.; Heiss, E. H. (2013). "12/15-Lipoxygenase contributes to Platelet-Derived Growth Factor- Induced Activation of Signal Transducer and Activator of Transcription 3". Journal of Biological Chemistry. doi:10.1074/jbc.M113.489013.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  10. ^ Hoch RV, Soriano P (2003). "Roles of PDGF in animal development". Development. 130 (20): 4769–4784. doi:10.1242/dev.00721. PMID 12952899.
  11. ^ Joukov V, Pajusola K, Kaipainen A, Saksela O, Alitalo K, Olofsson B, von Euler G, Orpana A, Pettersson RF, 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Lei KJ, Alitalo K, Maglione D, Guerriero V, Viglietto G, Ferraro MG, Aprelikova O, Chou JY, Persico MG, Del Vecchio S (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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ "PDGF Pathways". Retrieved 2007-11-17.
  15. ^ a b Alvarez, Ricardo H.; Kantarjian, Hagop M.; Cortes, Jorge E. (2006). "Biology of Platelet-Derived Growth Factor and Its Involvement in Disease". Mayo Clinic Proceedings. 81 (9): 1241–57. doi:10.4065/81.9.1241. PMID 16970222.
  16. ^ Song, G.; Ouyang, G.; Bao, S. (2005). "The Activation of Akt/PKB Signaling Pathway and Cell Survival". Journal of Cellular and Molecular Medicine. 9 (1): 59–71. doi:10.1111/j.1582-4934.2005.tb00337.x. PMID 15784165.
  17. ^ Pierce, G. F.; Mustoe, T. A.; Altrock, B. W.; Deuel, T. F.; Thomason, A. (1991). "Role of Platelet-Derived Growth Factor In Wound Healing". Journal of Cellular Biochemistry. 45 (4): 319. doi:10.1002/jcb.240450403.
  18. ^ a b c Kratchmarova, I.; Blagoev, B; Haack-Sorensen, M; Kassem, M; Mann, M (2005). "Mechanism of Divergent Growth Factor Effects in Mesenchymal Stem Cell Differentiation". Science. 308 (5727): 1472–7. doi:10.1126/science.1107627. PMID 15933201.
  19. ^ Hayashi, A. The New Standard of Care for Nonunions?. AAOS Now. 2009.
  20. ^ Barres BA, Hart IK, Coles HSR, 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ a b Proto-Oncogene+Proteins+c-sis at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  22. ^ McKinnon, Randall D.; Matsui, Toshimitsu; Dubois-Dalcq, Monique; Aaronson, Stuart A. (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.
  23. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Shulman T, Sauer FG, Jackman RM, Chang CN, Landolfi NF (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  25. ^ McClintock J, Chan I, Thaker S, Katial A, Taub F, Aotaki-Keen A, Hjelmeland L (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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ http://www.eurekalert.org/pub_releases/2011-10/jdrf-rmo101211.php[full citation needed]
  27. ^ http://med.stanford.edu/ism/2011/october/kim.html[full citation needed]

External links

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