Platelet-derived growth factor

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. Chemically Platelet-derived growth factor is dimeric glycoprotein composed of two A or two B chains.

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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 Vascular Endothelial Growth Factor.

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.^[1] The alpha type binds to PDGF-AA, PDGF-BB and PDGF-AB while the beta type PDGFR binds with high affinity to PDGF-BB and PDGF-AB.^[2] PDGF binds to PDGFRs ligand binding pocket located within the second and third immunoglobulin domains.^[3] 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 generally part of growth signaling complex, it plays a more profound role in controlling cell migration.^[4] 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 signalling. 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

PDGF plays a role in embryonic development, cell proliferation, cell migration, and angiogenesis.^[5] PDGF has also been linked to several diseases such as atherosclerosis, fibrosis and malignant diseases.^{[citation needed]}

In addition, PDGF is a required element in cellular division for fibroblast, a type of connective tissue cell.^{[citation needed]} In essence, the PDGFs allow a cell to skip the G1 checkpoints in order to divide.^{[citation needed]}

PDGF is also known to maintain proliferation of oligodendrocyte progenitor cells.^{[citation needed]}

History

PDGF was one of the first growth factors characterized, 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 has provided a market for protein receptor antagonists to treat disease. Such antagonists usually include specific antibodies that target the molecule of interest, which only act in a neutralizing manner.^{[citation needed]}

However, recent developments have allowed some biotechnology companies to circumvent this problem by creating specialized molecules that not only bind the protein of interest, but also destroy it in an enzymatic fashion.

The "c-Sis" oncogene is derived from PDGF.^[6][7]

See also

• Platelet-activating factor
• Platelet-derived growth factor receptor

References

1. ^ 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.
2. ^ Heidaran MA, Pierce JH, Yu JC, et al (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.
3. ^ Heidaran MA, Pierce JH, Jensen RA, Matsui T, Aaronson SA (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.
4. ^ 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. PMID 7706238.
5. ^ PDGF Pathways. Retrieved on 2007-11-17.
6. ^ 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. PMID 1537750.
7. ^ MeSH Proto-Oncogene+Proteins+c-sis