PDGFs and their receptors

Abstract

The platelet-derived growth factor (PDGF)/PDGFR receptor (PDGFR) family is essential for a vast array of physiological processes such as migration and proliferation of percityes that contribute to the formation and proper function of blood vessels. While ligand-dependent de-repression of the PDGFR's kinase activity is the major mode by which the PDGFR is activated, there are additional mechanisms to activate PDGFRs. Deregulated PDGFR activity contributes to various pathological conditions, and hence the PDGF/PDGFR family members are viable therapeutic targets. An increased appreciation of which PDGFR contributes to pathology, biomarkers that indicate the amplitude and mode of activation, and receptor-specific antagonists are necessary for the development of next-generation therapies that target the PDGF/PDGFR family.

Keywords: Activation of receptor tyrosine kinases; Indirect activation of PDGFR; Non-PDGFs; PDGF; PDGFR.

Figure 1.. PDGF-dependent activation of PDGFRs; the direct mode of activation.

PDGF drives assembly of monomeric PDGFRs into dimers, which de-represses the receptor’s intrinsic kinase activity. The activated PDGFRs initiates signal pathways that instruct cells to migrate and proliferate. Activated PDGFR dimers are internalized and degraded, which terminates signaling.

Figure 2.. The indirect mode of activating PDGFRα.

Growth factors outside of the PDGF family (non-PDGFs bind to their own receptors and initiate the indirect mode of activating PDGFRα. Reactive oxygen species (ROS) generated by NADPH oxidases stimulate Src family kinases (SFKs) to phosphorylate monomeric PDGFRα. In contrast to dimeric PDGFRs, activated monomeric PDGFRαs do not hasten their own internalization and degradation. This feature of the indirect mode of activating PDGFRα, together with an increase in mitochondrial ROS (due to suppression of autophagy/mitophagy) engages a feed-forward loop that enables the activity of PDGFRα to persist even after non-PDGF-dependent signaling has been extinguished. Indirect activation of PDGFRα results in a reduction in the level of p53, which promotes survival of cells.

Figure 3.. In the presence of both PDGF and non-PDGFs the PDGF-mediated mode of activation predominates.

Provided that there is enough PDGF to assemble PDGFRs into dimers, the PDGF-dependent mode of activation predominates even though non-PDGFs are present. This is the case because dimerized receptors are poor substrates for ROS activated SFKs. Furthermore, PDGF-mediated dimerization stimulates the internalization and degradation of PDGFRs; the half-life decreases from over 2 hours to 5 minutes.

Figure 4.. The indirect mode of activating PDGFRα predominates when all three classes of growth factors that engage PDGFRα are present.

VEGF competes with PDGF for binding to PDGFRs [5]. Because VEGF does not dimerize PDGFRs, it sustains a population of monomeric PDGFRs in the face of PDGF. It is this population that can undergo indirect activation. This outcome is concentration dependent; there must be enough VEGF to overcome the PDGF, which dimerizes PDGFRs and thereby prevents indirect activation (Fig 3).

Figure 5.. Hierarchy amongst the classes of growth factors that engage PDGFRα and are present in vitreous of patients afflicted by PVR.

VEGF competes with PDGF for binding to PDGFRs. PDGFs prevent non-PDGF-mediated activation of PDGFRα (the indirect mode) by dimerizing PDGFRs and accelerating their internalization and degradation. VEGF enables indirect activation of PDGFRα in the face of PDGF. These relationships are concentration dependent. Indirect activation of PDGFRα promotes PVR because it reduces the level of p53 and thereby enhances the viability of cells displaced into vitreous.