A Reactive Oxygen Species-Mediated, Self-Perpetuating Loop Persistently Activates Platelet-Derived Growth Factor Receptor α

Abstract

The platelet-derived growth factor (PDGF) receptors (PDGFRs) are central to a spectrum of human diseases. When PDGFRs are activated by PDGF, reactive oxygen species (ROS) and Src family kinases (SFKs) act downstream of PDGFRs to enhance PDGFmediated tyrosine phosphorylation of various signaling intermediates. In contrast to these firmly established principles of signal transduction, much less is known regarding the recently appreciated ability of ROS and SFKs to indirectly and chronically activate monomeric PDGF receptor ␣ (PDGFR␣) in the setting of a blinding condition called proliferative vitreoretinopathy (PVR). In this context, we made a series of discoveries that substantially expands our appreciation of epigenetic-based mechanisms to chronically activate PDGFR␣. Vitreous, which contains growth factors outside the PDGF family but little or no PDGFs, promoted formation of a unique SFK-PDGFR␣ complex that was dependent on SFK-mediated phosphorylation of PDGFR␣ and activated the receptor's kinase activity. While vitreous engaged a total of five receptor tyrosine kinases, PDGFR␣ was the only one that was activated persistently (at least 16 h). Prolonged activation of PDGFR␣ involved mTOR-mediated inhibition of autophagy and accumulation of mitochondrial ROS. These findings reveal that growth factor-containing biological fluids, such as vitreous, are able to tirelessly activate PDGFR␣ by engaging a ROS-mediated, self-perpetuating loop.

Ligand-Independent Activation of Platelet-Derived Growth Factor Receptor β during Human Immunodeficiency Virus–Transactivator of Transcription and Cocaine-Mediated Smooth Muscle Hyperplasia

“…Lysophosphatidic acid has previously been reported to cause ligand-independent activation of PDGFRb (43). PDGFRa has been reported to be activated by ROS upon treatment of cells with growth factors from other than the PDGF family (44). Likewise, we now document involvement of ROS in cocaine-and Tat-mediated ligandindependent activation of PDGFRb at Y934.…”

RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology

“…RV contains a plethora of growth factors outside the PDGF family (non-PDGFs) and no PDGFs (42,43). Exposing cells to RV directly activates receptor tyrosine kinases, such as ErbB1, ErbB2, IGF-1R, and insulin receptor, and indirectly activates PDGFR␣ (26). RV promoted association of RasGAP with PDGFR␤ but not PDGFR␣ or F771 PDGFR␤ (Fig.…”

“…This is because it has not been dimerized by PDGF, which greatly shortens its half-life. Furthermore, indirectly activated PDGFR␣ engages signaling events that suppress autophagy, and thereby elevate mitochondrial ROS, and perpetuates activation (26). Thus, indirect activation of PDGFR␣ involves monomeric receptors, which are activated persistently because of a mitochondrial-ROS-driven feed-forward loop.…”

“…The key elements of this intracellular route include non-PDGF (growth factors outside the PDGF family)-mediated elevation of reactive oxygen species (ROS) and activation of Src family kinases, which phosphorylate and activate monomeric PDGFR␣ (25,26). Unlike directly activated PDGFR␣, which is rapidly extinguished (its half-life is less than 5 min [27,28]), indirectly activated PDGFR␣ signals persistently (28).…”

Reactive Oxygen Species: The Good and the Bad

“…PDGF and thrombin are both agonists to help cell proliferation, and both agonists require ROS in their mechanisms to amplify and further their signal for greater cell growth [30]. ROS also plays an important role in the expression of transcription nuclear factor-kB, which helps the body's inflammatory process by activating the monocyte chemotactic protein-1 (MCP-1) and interleukin-6 [31].…”