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

作者：Lei Hetian; Kazlauskas Andrius^*

来源：Molecular and Cellular Biology, 2014, 34(1): 110-122.

DOI：10.1128/MCB.00839-13

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 alpha (PDGFR alpha) 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 alpha. Vitreous, which contains growth factors outside the PDGF family but little or no PDGFs, promoted formation of a unique SFK-PDGFR alpha complex that was dependent on SFK-mediated phosphorylation of PDGFR alpha and activated the receptor's kinase activity. While vitreous engaged a total of five receptor tyrosine kinases, PDGFR alpha was the only one that was activated persistently (at least 16 h). Prolonged activation of PDGFR alpha 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 alpha by engaging a ROS-mediated, self-perpetuating loop.

• 出版日期2014-1