Platelet-derived growth factor (PDGF) is a family of disulfide-bonded dimeric molecules of A-, B-, C- and D-polypeptide chains (PDGF-AA, -AB, -BB, -CC and -DD). PDGF isoforms stimulate proliferation, survival and motility of connective tissue cells, and certain other cell types.

PDGFs have important roles during the embryonal development to stimulate the differentiation and proliferation of specific mesenchymal cell types in different organs, such as smooth muscle cells and pericytes of blood vessels, mesangial cells in the kidney, alveolar myofibroblasts of the lung, and glial cells of the central nervous system. In the adult, PDGF is important for wound healing and for the regulation of the interstitial fluid pressure of tissues. Overactivity of PDGF is associated with malignancies, and other diseases characterized by excessive cell proliferation, including atherosclerosis and fibrotic conditions.

The cellular effects of PDGF are mediated by α- and β-tyrosine kinase receptors. Each receptor contains five extracellular Ig-like domains and an intracellular kinase domain which contains an inserted sequence of about 100 amino acid residues without similarity to kinases. The PDGF chains bind the receptors with different specificities. Thus, the α-receptor binds A-, B- and C-chains, whereas the β-receptor binds B- and D-chains. Ligand binding induces receptor dimerization; depending on the stimulating isoform, αα-homodimers, ββ-homodimers or αβ-heterodimers are formed. Within the dimers, the receptors are autophosphorylated in trans, which has two important functions: Autophosphorylation of a conserved tyrosine residue in the activation loop of the kinase domain causes activation of the kinase, and autophosphorylation of a number of tyrosine residues outside the kinase domain creates binding sites for downstream SH2 domain-containing molecules; the binding and activation of such molecules initiates a number of signaling pathways which leads to cell growth, survival and migration.

More than 10 families of SH2 domain proteins bind to the α- and β-receptors. They are of different kinds, i.e. molecules with associated enzymatic activities which are activated and/or attracted to the inner leaflet of the cell membrane by the receptors, members of the Stat family of transcription factors which after activation are translocated to the nucleus where they effect transcription of specific genes, and adaptor molecules which mediate interactions with other signaling components. Examples of enzymes activated by PDGF receptors are the tyrosine kinase Src, phospholipase C-γ (PLC-γ), phosphatidylinositol-3’-kinase (PI3K), GTPase activating protein (GAP) for Ras, and the tyrosine phosphatase SHP-2. Examples of adaptors include Shc, Nck, Grb2, Grb7 and Crk. Transient inhibition of tyrosine phosphatases through PI3K-dependent production of H2O2 delays dephosphorylation and enhances the signals.

The α- and β-receptors have overlapping but distinct signaling capacities, which are mainly dictated by which SH2-domain molecules they bind. Thus, both receptors stimulate cell growth, but whereas the β-receptor potently stimulates chemotaxis, the α-receptor inhibits chemotaxis in certain cell types. In vivo experiments in mice, in which the cytoplasmic domains between the α- and β-receptors were swapped, revealed that the β-receptor intracellular domain can fully substitute for the α-receptor’s. However, replacement of the β-receptor’s cytoplasmic domain with that of the α-receptor causes abnormalities in vascular smooth muscle cell development and function.

There are examples that overactivity of PDGF receptors through enhanced autocrine ligand stimulation contributes to malignancies, e.g. dermatofibrosarcoma protuberans, in which the PDGF B-chain gene is fused to a collagen gene leading to the production of a fusion protein which is processed to PDGF-BB. There are also examples of activation of PDGF receptors by mutation in certain tumor types. Thus, translocation of the genes for PDGF α- or β-receptors occur in hypereosinophilic syndrome and atypic chronic myeloic leukemias. In these cases, fusion proteins are formed between the kinase domains of the receptors and other molecules which cause constitutive dimerization and activation of the kinases. In a subfraction of gastrointestinal stromal tumors, the activation loop of the α-receptor is mutated, and in a subfraction of glioblastoma multiforme, the α-receptor gene is amplified. In each one of these cases the overactive receptor causes constitutive growth and survival signals which contribute to malignant transformation. Treatment of patients with certain of these diseases with selective PDGF receptor tyrosine kinase inhibitors, has given promising results.

The Table below contains accepted modulators and additional information. For a list of additional products, see the Materials section below.

Table 1
Table 2

Footnotes

a) Can form homodimers of the respective receptor types. In addition, all PDGF isoforms, except PDGF-AA, can form PDGFRa/PDGFRb heterodimers in cells expressing both receptor types.

Materials
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References

1.
Basciani S, Mariani S, Spera G, Gnessi L. 2010. Role of Platelet-Derived Growth Factors in the Testis. 31(6):916-939. http://dx.doi.org/10.1210/er.2010-0004
2.
Claesson-Welsh L, Eriksson A, Westermark B, Heldin CH. 1989. cDNA cloning and expression of the human A-type platelet-derived growth factor (PDGF) receptor establishes structural similarity to the B-type PDGF receptor.. Proceedings of the National Academy of Sciences. 86(13):4917-4921. http://dx.doi.org/10.1073/pnas.86.13.4917
3.
Heldin C, Westermark B. 1999. Mechanism of Action and In Vivo Role of Platelet-Derived Growth Factor. Physiological Reviews. 79(4):1283-1316. http://dx.doi.org/10.1152/physrev.1999.79.4.1283
4.
Heldin C. 2004. Platelet-derived growth factor?an introduction. Cytokine & Growth Factor Reviews. 15(4):195-196. http://dx.doi.org/10.1016/j.cytogfr.2004.03.001
5.
Jayson G, Parker G, Mullamitha S, Valle J, Saunders M, Broughton L, Lawrance J, Carrington B, Roberts C, Issa B, et al. 2005. Blockade of Platelet-Derived Growth Factor Receptor-Beta by CDP860, a Humanized, PEGylated di-Fab', Leads to Fluid Accumulation and Is Associated With Increased Tumor Vascularized Volume. JCO. 23(5):973-981. http://dx.doi.org/10.1200/jco.2005.01.032
6.
Kazlauskas A, Cooper JA. 1989. Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins. Cell. 58(6):1121-1133. http://dx.doi.org/10.1016/0092-8674(89)90510-2
7.
Klinghoffer RA, Mueting-Nelsen PF, Faerman A, Shani M, Soriano P. 2001. The Two PDGF Receptors Maintain Conserved Signaling In Vivo despite Divergent Embryological Functions. Molecular Cell. 7(2):343-354. http://dx.doi.org/10.1016/s1097-2765(01)00182-4
8.
A. Kono S, E. Heasley L, C. Doebele R, R. Camidge D. 2012. Adding to the Mix: Fibroblast Growth Factor and Platelet-Derived Growth Factor Receptor Pathways as Targets in Non ? small Cell Lung Cancer. CCDT. 12(2):107-123. http://dx.doi.org/10.2174/156800912799095144
9.
Malhotra B, Schuetze SM. 2012. Dermatofibrosarcoma protruberans treatment with platelet-derived growth factor receptor inhibitor. Current Opinion in Oncology. 24(4):419-424. http://dx.doi.org/10.1097/cco.0b013e328353d78d
10.
Matsui T, Heidaran M, Miki T, Popescu N, La Rochelle W, Kraus M, Pierce J, Aaronson S. 1989. Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes. Science. 243(4892):800-804. http://dx.doi.org/10.1126/science.2536956
11.
Morris PG, Abrey LE. 2010. Novel targeted agents for platelet-derived growth factor receptor and c-KIT in malignant gliomas. Targ Oncol. 5(3):193-200. http://dx.doi.org/10.1007/s11523-010-0160-7
12.
Nakagawa T, Inoue H, Sasahara M. 2012. Platelet-derived growth factor and renal disease. Current Opinion in Nephrology and Hypertension. 21(1):80-85. http://dx.doi.org/10.1097/mnh.0b013e32834db4d3
13.
Pietras K, Sjöblom T, Rubin K, Heldin C, Östman A. 2003. PDGF receptors as cancer drug targets. Cancer Cell. 3(5):439-443. http://dx.doi.org/10.1016/s1535-6108(03)00089-8
14.
Soriano P. 1994. Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice.. Genes & Development. 8(16):1888-1896. http://dx.doi.org/10.1101/gad.8.16.1888
15.
Soriano P. 1997. The PDGF alpha receptor is required for neural crest cell development and for normal patterning of the somites Development.. 124(14):2691-700.
16.
Sundaresan M, Yu Z, Ferrans VJ, Irani K, Finkel T. 1995. Requirement for Generation of H(2)O(2) for Platelet-Derived Growth Factor Signal Tran sduction. Science. 270(5234):296-299. http://dx.doi.org/10.1126/science.270.5234.296
17.
van Roeyen CR, Ostendorf T, Floege J. 2012. The platelet-derived growth factor system in renal disease: An emerging role of endogenous inhibitors. European Journal of Cell Biology. 91(6-7):542-551. http://dx.doi.org/10.1016/j.ejcb.2011.07.003
18.
Yarden Y, Escobedo JA, Kuang W, Yang-Feng TL, Daniel TO, Tremble PM, Chen EY, Ando ME, Harkins RN, Francke U, et al. 1986. Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature. 323(6085):226-232. http://dx.doi.org/10.1038/323226a0

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