Pdgf

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Growth factor from thrombocytes; platelet derived growth factor; Platelet-derived growth factor BB

History
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In 1974 it was discovered that a serum growth factor produced by platelets activates fibroblasts, smooth muscle cells and glial cells (Kohler N et al. 1974). This factor was called "platelet-derived growth factor" because of its origin. Originally, the family consisted of three PDGF members - PDGF-AA, PDGFAB and PDGF-BB - encoded by two genes, PDGF-A and, PDGF-B (Heldin CH et al. (1999). This view existed for about 15 years until two additional PDGF genes and proteins - PDGF-C (Li et al. 2000) and PDGF-D (Bergsten et al. 2001) - were identified.

Definition
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PDGF is the acronym for "platelet-derived growth factor". PDGF is a generic term for a family of four gene products that are functionally and structurally closely related to the family of VEGF (Vascular Endothelial Growth Factor) growth factors. This growth factor family plays an essential role in embryonic development and wound healing in adults.

The currently known PDGF genes and their associated peptide gene products (growth factors) belong to a family of structurally and functionally related peptides (Fredriksson et al. 2004), to which VEGF growth factors also belong. Both peptide groups are conserved throughout the animal kingdom and are functionally closely related, so that they are often grouped together as a common PDGF/VEGF family. In invertebrates, the molecules of these two families cannot easily be distinguished from each other. In this respect, they are also referred to as PVFs (PDGF/VEGF-like growth factors).

Classification
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The PDGF family is a product of four gene products and consists of five dimeric isoforms:

  • PDGF-AA
  • PDGF-BB
  • PDGF-CC
  • PDGF-DD

and the PDGF-AB heterodimer.

All members carry a core growth factor domain that contains a conserved set of cysteine residues. The core domain is necessary and sufficient for receptor binding and activation.

The classification into PDGFs or VEGFs is based on receptor binding. It was generally assumed that PDGFs and VEGFs are selective for their own receptors. This view was challenged by the evidence that VEGF-A can bind to and activate PDGF receptors of mesenchymal bone marrow stem cells (Ball et al. 2007). This also calls into question whether VEGFs are mainly effective as mitogens on endothelial cells, whereas PDGFs activate mesenchymal cells for growth. A further challenge to the functional differences between PDGFs and VEGFs arises from the findings that VEGF-C and PDGF-A both regulate oligodendrocyte development, but via different receptors. VEGFs and PDGFs also appear to be both effective in haematopoietic development, neurogenesis and neuroprotection.

General information
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Functions for PDGFR signaling were found in blood vessel formation and in early hematopoiesis. PDGF signalling is involved in a number of diseases. Autocrine activation of PDGF signaling pathways has been observed in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signalling is often detectable in epithelial cancers, where current recruitment is triggered, affecting tumour growth, angiogenesis, invasion and metastasis. PDGFs control pathological mesenchymal responses in vascular diseases such as atherosclerosis, restenosis, pulmonary hypertension and retinal diseases, and in fibrotic diseases including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis and cardiac fibrosis.

The growth factors usually occur as dimers (homo- or heterodimers) connected by two disulfide bridges. They thus bind two receptors (PDGFR) each. Through this binding they cause a dimerisation of the receptors, which in this state can phosphorylate the tyrosine bound in the intracellular domain. Stimulated in this way, intracellular signalling pathways are activated, leading to cell proliferation and anti-apoptosis.

Pathophysiology
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PDGF growth factors mediate their effects by binding and activating their receptor protein tyrosine kinases encoded by two genes: PDGFRA and PDGFRB. The functional receptors consist of the homodimers PDGFRα / α and PDGFRβ / β and the heterodimer PDGFRα / β (see figure). Although PDGF signal transduction is most closely associated with mesenchymal cells, PDGFs and PDGF receptors are widely distributed in the mammalian central nervous system. PDGF receptors contain an extracellular domain consisting of five immunoglobulin-like domains (Ig-d1 / 2/3/4/5), a transmembrane segment, a juxtamembrane segment, and a protein tyrosine kinase domain containing an insert of about 100 amino acid residues and a carboxyterminal tail.

General therapy
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Although rare, activating mutations in the genes for PDGF or PDGF receptors are documented in various neoplasms, including dermatofibrosarcoma protuberans (DFSP) and various gastrointestinal stromal tumors (GIST). In most neoplastic diseases, the expression and effect of PDGF appears to affect the tumor stroma. More than 10 PDGFRα / β-multicinase antagonists have been approved for the treatment of several neoplastic diseases and interstitial lung fibrosis.

Note(s)
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Human PDGF was originally identified as a disulfide bound dimer of two different polypeptide chains A and B, which were chemically separable. For the B chain (PDGF-B), a close homology between PDGF-B and the product of the retroviral oncogene v-sis of the simian sarcoma virus (SSV) was discovered (Doolittle et al. 1983). It was later confirmed that the human cellular counterpart (c-sis) was identical to PDGF-B.

Literature
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  1. Andrae J et al (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276-1312.
  2. Ball SG et al (2007) Vascular endothelial growth factor can signal through platelet-derived growth factor receptors. J. Cell Biol. 177: 489–500.
  3. Bergsten E et al (2001) PDGF-D is a specific, protease-activated ligand for the PDGF -receptor. Nat. Cell Biol. 3: 512-516.
  4. Doolittle RF et al (1083) Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 221: 275-277.
  5. Fredriksson L et al (2004) The PDGF family: Four gene products form five dimeric isoforms. Cytokine Growth Factor Rev. 15: 197-204.
  6. Fredriksson L et al. (2004) Tissue plasminogen activator is a potent activator of PDGFCC. EMBO J. 23: 3793-3802.
  7. Heldin CH et al (1999) Mechanism of action and in vivo role of platelet-derived growth facto. In: Physiol Rev 79: 1283-1316.
  8. Kohler N et al (1974) Platelets as a source of fibroblast growth-promoting activity. Exp. Cell Res. 87: 297-301.
  9. Li X et al (2000) PDGF-C is a new protease-activated ligand for the PDGF-receptor. Nat. Cell Biol. 2: 302-309.

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Last updated on: 29.10.2020