- Platelet-derived growth factor
Platelet-derived growth factor (PDGF) Identifiers Symbol PDGF Pfam PF00341 InterPro IPR000072 PROSITE PDOC00222 SCOP 1pdg Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary
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.
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.
Human genes encoding proteins that belong to the platelet-derived growth factor family include:
- Platelet-activating factor
- Platelet-derived growth factor receptor
- atheroma platelet involvement in smooth muscle proliferation
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- ^ a b MeSH Proto-Oncogene+Proteins+c-sis
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Growth factors Fibroblast EGF-like domain TGFβ pathway Insulin-like Platelet-derived Vascular endothelial Other B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp) Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes LigandONCO: c-Sis/PDGF · HGF ReceptorTSP: CDH1TSP: PTCH1TSP: TGF beta receptor 2 Intracellular signaling P+PsONCO: Beta-catenin · TSP: APCHippo signaling pathwayOther/unknown NucleusTSP: VHL · ONCO: CBL - MDM2 Mitochondria Other/ungrouped
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