Structural and functional aspects of the receptors for platelet-derived growth factor.
Platelet-derived growth factor (PDGF) is a 30 kDa dimer of disulfide-bonded A and B chains. Three isoforms of PDGF have been isolated (PDGF-AA, PDGF-AB and PDGF-BB). These bind with different affinities and specificities to two structurally related cell surface receptors, viz. the alpha-receptor and the beta-receptor. The receptors are transmembrane proteins with an intracellular, ligand-stimulatable protein tyrosine kinase domain. Activation of the receptors is intimately associated with receptor dimerization, and available data suggest that PDGF is a divalent ligand such that one molecule of PDGF binds and dimerizes two receptor molecules. Stimulation of PDGF receptors leads to a cascade of cellular events, which have been shown to require an intact receptor tyrosine kinase activity. However, ligand-induced internalization and degradation of the beta-receptor occur essentially independent of the receptor kinase activity. Receptor activation leads to the phosphorylation on tyrosine residues of three enzymes, probably by direct phosphorylation: phospholipase C-gamma, phosphatidylinositol 3' kinase and Raf-1. In certain cells, PDGF beta-receptor expression is inducible such that cells in normal tissue in vivo do not express receptors; only in inflammatory lesions or when cells are explanted in vitro, are receptors being expressed. Transformation by the v-sis oncogene is mediated by an autocrine PDGF-like growth factor. Although both the alpha- and beta-receptors are structurally related to the v-fms and v-kit oncogenes, it is not known if the PDGF receptors have a transforming potential. In conclusion, the finding of three isoforms of PDGF that interact with two structurally related receptors implies a finely tuned regulatory network, the role of which in cell growth and transformation remains to be clarified.
Westermark
B
B
Department of Pathology, University Hospital, Uppsala, Sweden.
Claesson-Welsh
L
L
Heldin
C H
CH
D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D010982:Platelet-Derived Growth Factor; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor
D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D017479:Receptors, Platelet-Derived Growth Factor