Platelet-derived growth factor (PDGF), a basic protein stored in the a granules of platelets, acts as a chemoattractant and mitogen for fibroblastic cells.
Two peptides related to platelet-derived growth factor are present in human wound fluid: A study shows that the analysis of wound fluid collected from patients after radical mastectomy revealed the presence of two PDGF-related peptides of 16-17 kDa and 34-36 kDa. These PDGF-related peptides were purified by using anti-PDGF immunoaffinity techniques and found to possess both chemotactic and mitogenic activities for NIH 3T3 cells in vitro. Furthermore it was not able to detect authentic native PDGF (30 kDa) or PDGF A or B chain in any of the wound-fluid samples examined. This suggests that PDGF-related peptides are present in normal human wound fluid, whereas PDGF A- and B-chain peptides are absent or only present in trace amounts relative to the total PDGF-related biological activity1.
PDGF is a cationic glycoprotein of approximately 30 kDa, composed of two subunits. These subunit chains are termed A (18 kDa) and B (12-14 kDa)2. The mature parts of the A- and B-chains of PDGF are ~100 amino acid residues long and show ~60% amino acid sequence identity. Eight cysteine residues are perfectly conserved between the two chains. Two of the cysteine residues (the second and the fourth) are involved in cysteine bonds between the two subunits in the PDGF dimer, and the other six are engaged in intrachain disulfide bonds (the first pairs with the sixth, the third with the seventh, and the fifth with the eighth)3.
Three isoforms of PDGF, AA, BB homodimers and AB heterodimer are distributed in the different tissues and cell lines suggesting that these isoforms have different functions. Two types of PDGF receptors alpha, and beta with Mr of 160-180 kDa are seen on the cell surface. PDGFR alpha can bind to both A and B subunits of the PDGD, while PDGFR beta, only B subunit2.
Mode of Action
Binding of PDGF induces dimerization of the receptors in vitro and in vivo, as shown by several techniques. Depending on the PDGF isoform, homo- or heterodimers of receptors are formed . PDGF-AA induces a-a homodimers, PDGF-AB induces a-a homodimers and a-ß heterodimers, and PDGF-BB induces all three types (a-a, a-ß, and ß-ß) of dimers. Dimerization is accompanied by, and might be a prerequisite for, activation of the kinase4. Kinase activation is visualized as tyrosine phosphorylation of the receptor molecules. In conjunction with dimerization and kinase activation, the receptor molecules undergo conformational changes. These all leads to scenario of events where receptor dimerization and accompanying conformational changes allow a basal kinase activity to phosphorylate a critical tyrosine residue, thereby unlocking the kinase, leading to full enzymatic activity directed toward other tyrosine residues in the receptor molecules as well as other substrates for the kinase5.
Platelet-derived growth factor receptors: a therapeutic target in solid tumors: PDGF signals through a cell surface tyrosine kinase receptor to stimulate various cellular functions including growth, proliferation, and differentiation. PDGF expression has been shown in a number of different solid tumors, from glioblastomas to prostate carcinomas. In these various tumor types, the biologic role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and even angiogenesis.
The tyrosine kinase inhibitor, such as imatinib mesylate blocks activity of the Bcr-Abl oncoprotein, and was recently approved for treatment of chronic myeloid leukemia. Imatinib mesylate is also a potent inhibitor of the PDGF-R kinase and is currently being evaluated for the treatment of PDGF-responsive tumors such as prostate cancer6.
Platelet-derived growth factor as a mediator of normal and neoplastic cell proliferation: Human platelet-derived growth factor is the major mitogen in serum for connective-tissue-derived cells in culture. It is composed of two disulphide-linked polypeptide chains, named A and B. The B-chain is virtually identical to part of the transforming protein of simian sarcoma virus (SSV), implying that SSV-transformation is mediated by a PDGF-like growth factor. This notion is supported by the finding that specific as well as nonspecific inhibitors of PDGF-action are efficient inhibitors of SSV-transformation and revert the transformed phenotype of SSV-transformed cells. Expression of the genes encoding the PDGF subunits and production of PDGF-like growth factors is a common feature of human sarcoma cell lines, suggesting a role of PDGF in the pathogenesis of sarcomas, although direct support in favor of this notion is lacking. An involvement of PDGF in autocrine and paracrine stimulation of normal cell growth is suggested by the finding that responsive (arterial smooth muscle cells and placental cytotrophoblasts) as well as nonresponsive (endothelial cells and macrophages) cells produce PDGF-like growth factors. This implies that, PDGF-like growth factors may be widely implicated in normal as well as neoplastic growth processes7.
1. Matsuoka J, Grotendorst GR. (1989). Two peptides related to platelet-derived growth factor are present in human wound fluid. PNAS., 86(12):4416-4420.
2. Kaji K (1992). Function, molecular structure and gene expression regulation of Platelet-derived growth factor. Nippon Rinsho., 50(8):1902-1909.
3. Haniu M, Hsieh P, Rohde MF, Kenney WC.(1994). Characterization of disulfide linkages in platelet-derived growth factor AA. Arch. Biochem. Biophys., 310(2): 433-439.
4. Bishayee S, Majumdar S, Khire J, Das M. (1989). Ligand-induced dimerization of the platelet-derived growth factor receptor. Monomer-dimer interconversion occurs independent of receptor phosphorylation. J. Biol. Chem., 264(20): 11699-11705.
5. Lena Claesson-Welsh (1994). Platelet-derived Growth Factor Receptor Signals. J Biol Chem., 269 (51):32023-32026.
6. George D (2001). Platelet-derived growth factor receptors: a therapeutic target in solid tumors. Semin Oncol., 28 (5):27-33.
7. Westermark B, Heldin CH (1986). Platelet-derived growth factor as a mediator of normal and neoplastic cell proliferation. Med. Oncol. Tumor. Pharmacother., 3 (3-4):177-183.
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