Platelet-derived growth factor
|Platelet-derived growth factor (PDGF)|
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 dimeric glycoprotein composed of two A (-AA) or two B (-BB) chains or a combination of the two (-AB).
PDGF 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.
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.
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. 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. PDGF binds to PDGFRs ligand binding pocket located within the second and third immunoglobulin domains. 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. 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. 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.
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. Other growth factors in this family include vascular endothelial growth factors B and C (VEGF-B, VEGF-C) which are active in angiogenesis and endothelial cell growth, and placenta growth factor (PlGF) which is also active in angiogenesis.
PDGF plays a role in embryonic development, cell proliferation, cell migration, and angiogenesis. PDGF has also been linked to several diseases such as atherosclerosis, fibrosis and malignant diseases.
In addition, PDGF is a required element in cellular division for fibroblast, a type of connective tissue cell. In essence, the PDGFs allow a cell to skip the G1 checkpoints in order to divide.
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.
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.
Family members 
Human genes encoding proteins that belong to the platelet-derived growth factor family include:
See also 
- Platelet-activating factor
- Platelet-derived growth factor receptor
- atheroma platelet involvement in smooth muscle proliferation
- 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.
- Heldin CH (1992). "Structural and functional studies on platelet-derived growth factor". EMBO J. 11 (12): 4251–4259. PMC 556997. PMID 1425569.
- Minarcik, John. "Global Path Course: Video". Retrieved 2011-06-27.
- Kumar, Vinay (2010). Robbins and Coltran Pathologic Basis of Disease. China: Elsevier. pp. 88–89. ISBN 978-1-4160-3121-5.
- 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.
- 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.
- 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.
- 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.
- Hoch RV, Soriano P (2003). "Roles of PDGF in animal development". Development 130 (20): 4769–4784. doi:10.1242/dev.00721. PMID 12952899.
- 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.
- 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.
- 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.
- "PDGF Pathways". Retrieved 2007-11-17.
- 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.
- Proto-Oncogene Proteins c-sis at the US National Library of Medicine Medical Subject Headings (MeSH)
- 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.
- 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.
- 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.
- platelet-derived growth factor at the US National Library of Medicine Medical Subject Headings (MeSH)
- platelet-derived+growth+factor at eMedicine Dictionary