Platelet-Derived Growth Factor and Lung Development

Abstract

Platelet-derived growth factor (PDGF) is a potent stimulant of connective-tissue cell proliferation and migration. PDGF is a dimer composed of two highly homologous peptide chains, A and B, joined by disulfide bonds. Three different forms of PDGF exist in vivo: PDGF-AA, PDGF-AB, and PDGF-BB. The three isoforms of PDGF differ in their functional properties as well as in their secretory behavior (1). The A-chain and B-chain precursors both contain signal sequences that allow PDGF-AA and PDGF-AB to be rapidly secreted from their producer cell. A 24-kD form of PDGF-BB remains, to a large extent, associated with the producer cell, and relatively small amounts of the 30-kD PDGF-BB are secreted (2,3).Homodimeric isoforms of PDGF are widely expressed by normal cell lines and tissue. As mentioned, PDGF is well recognized to be a potent mitogen for cells of mesenchymal origin, but recent findings have shown that it may also induce growth of some specialized epithelial cells (4), capillary endothelial cells (5),and some types of white blood cells (6). In analogy with the different PDGF chains, two different high-affinity PDGF receptors, α and β, are expressed by many cell types (7). The PDGF receptor is a representative of a class of receptor tyrosine kinases distinct from other receptors because the catalytic domain is split by an intervening stretch of approx 100 amino acids, and the extracellular region is organized into immunoglobulinlike repeats (8). PDGF-BB can bind to both PDGF α- and β-receptors, whereas PDGF-AA binds only the α-receptor (9). Upon binding of a PDGF dimer to its receptor, two appropriate PDGF receptor subunits are brought together, and a number of specific tyrosine residues on the receptor subunits are phosphorylated (10).This receptor tyrosine autophosphorylation is manifested as a transphosphorylation between the two receptor dimers. There are 16 known autophosphorylated tyrosine residues in the β-receptor for PDGF. One site a conserved tyrosine residue localized inside the kinase domain (Tyr857). Mutation of this residue to a phenylalanine residue gives a receptor with a lowered kinase activity, suggesting that phosphorylation of Tyr857 is important for activation of the kinase (11). A total of 11 of the 15 tyrosine residues in the noncatalytic part of the receptor are phosphorylated. Mapping data of phosphorylated residues on the α-receptor are less well characterized (12). The receptor tyrosine phosphorylation creates binding sites for several molecules that interact with specific phosphotyrosines through their SH2 (src homology 2) domains (13). The SH2 domain proteins that interact with the PDGF β-receptor fall into two categories: (i) molecules with enzymatic or other activity, and (ii) adaptor molecules which serve to connect the receptor with other molecules (14).Phospholipase Cγ (PLCγ), Ras GTPase-activating protein (Ras-GAP), the regulatory subunit of phosphatidylinositol 3-kinase (p85 of PI 3-kinase), growth factor receptor-bound protein 2 (GRB2), the tyrosine-specific phosphatase Syp, Src homology and collagen protein (Shc), and members of the Src family have been found to bind specific phosphotyrosines in the activated PDGF β-receptor (15).Receptor dimerization and the subsequent receptor autophosphorylation and tyrosine-kinase activation are required for transduction of the signals leading to proliferation and migration (16). The ability of homo- and heterodimers of PDGF to induce mitogenesis and migration depends on both the PDGF dimer present and the relative numbers of the two different PDGF receptor subunits on the responding cell (17).There is considerable cross-talk between different signaling pathways and stimulatory and inhibitory signals often are initiated in parallel (18–20).