Since there are five structurally distinct PDGF ligands that signal differentially through three forms of the PDGF receptor, it is clear that cell context is of great importance in understanding the intracellular signaling of any one ligand-receptor interaction. Add to this the secretion of PDGF-CC and PDGF-DD in latent forms that must be proteolytically activated in the extracellular matrix of a given cell, and the potential for heterogeneity in cell responses is expanded even further. As shown in Figure 1, there are ample docking sites available among the 11 tyrosine residues on PDGFRα and 13 on PDGFRβ that are phosphorylated upon receptor activation. The figure shows the specific sites to which various proteins are able to bind with high affinity. These proteins include enzymes such as PLCγ-1 and PI3-kinase; members of the STAT family of transcription factors; and members of the GRB family of adaptor proteins. Most of the associations between these proteins and their sites on the receptor occur through SH-2 (Src-homology 2) domains on the binding proteins. It is important to note that the exact proteins that are bound to the activated receptor in any particular cell, and therefore the pathways initiated, will depend on the availability of the proteins and, most likely, the particular ligand-receptor complex present in the cell.
Fig1. Proximal signaling events at the PDGF receptor. The dimerized PDGF contains numerous tyrosines that can undergo phosphorylation when the receptor is activated. These are shown by orange circles, 11 on each α protomer and 13 on each β protomer. Each of the sites interacts, as indicated by a solid line, specifically with one or more proteins to initiate the intracellular events that will lead to the biological response. These proteins may be enzymes (green), transcription factors (purple), or adaptor proteins (blue). SFK, Src family kinases; PI3K, phosphatidylinositol 3′-kinase; PLCγ-1, phospholipase Cγ-1; SHP-2, SH2 domain-containing protein tyrosine phosphatase-2; RasGAP, Ras GTPase activating protein; STAT, signal transducer and activator of transcription; GRB, growth factor receptor bound; Crk, CT10 regulator of kinase.
Among the outcomes of PDGF signaling are proliferation, chemotaxis, survival in the form of protection from apoptosis, and, in some cells, differentiation. The examples below will indicate that the response of a given cell to a particular ligand depends to a great extent on which PDGF receptor(s) are present as the three forms are dis tinct from one another in their binding and signaling properties. In cells with the ββ receptor, GRB2, through the recruitment of Ras and SOS initiates the MAP kinase pathway to stimulate proliferation. RasGAP interaction with the β PDGFR stimulates Ras GTPase activity, rendering Ras inactive and thereby countering the Ras-mediated stimulation of proliferation.
In contrast, GRB2 interaction with the αα receptor does not lead to Ras so other pathways, possibly PI3 kinase, account for increased proliferation in response to PDGF in cells with the αα PDGFR. Thus, the proliferative response of a given cell to PDGF will depend on the receptor types present and the balance between positive and negative influences on the process.
The ability of α and β PDGFRs to stimulate chemo taxis also differ; PDGFR ββ and PDGFRαβ potently stimulate chemotaxis, whereas the ability of PDGFRαα to do so is open to question. Both PI3 kinase and PLCγ1 mediate pathways that contribute to the chemotactic response which involves marked cytoskeletal changes and cell adhesion properties. This role of PDGF in chemotaxis, bringing new cells to a particular site, is crucial to its role in capillary formation during embryonic development and in wound healing.
