Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt Precursor Cell Function

Abstract

Identification of common mechanistic principles that shed light on the action of the many chemically diverse toxicants to which we are exposed is of central importance in understanding how toxicants disrupt normal cellular function and in developing more effective means of protecting against such effects. Of particular importance is identifying mechanisms operative at environmentally relevant toxicant exposure levels. Chemically diverse toxicants exhibit striking convergence, at environmentally relevant exposure levels, on pathway-specific disruption of receptor tyrosine kinase (RTK) signaling required for cell division in central nervous system (CNS) progenitor cells. Relatively small toxicant-induced increases in oxidative status are associated with Fyn kinase activation, leading to secondary activation of the c-Cbl ubiquitin ligase. Fyn/c-Cbl pathway activation by these pro-oxidative changes causes specific reductions, in vitro and in vivo, in levels of the c-Cbl target platelet-derived growth factor receptor-α and other c-Cbl targets, but not of the TrkC RTK (which is not a c-Cbl target). Sequential Fyn and c-Cbl activation, with consequent pathway-specific suppression of RTK signaling, is induced by levels of methylmercury and lead that affect large segments of the population, as well as by paraquat, an organic herbicide. Our results identify a novel regulatory pathway of oxidant-mediated Fyn/c-Cbl activation as a shared mechanism of action of chemically diverse toxicants at environmentally relevant levels, and as a means by which increased oxidative status may disrupt mitogenic signaling. These results provide one of a small number of general mechanistic principles in toxicology, and the only such principle integrating toxicology, precursor cell biology, redox biology, and signaling pathway analysis in a predictive framework of broad potential relevance to the understanding of pro-oxidant–mediated disruption of normal development.

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

“…methylmercury, lead, paraquat) in the absence of differentiating factors in the medium. 57,58 However, when differentiating factors are added to the medium, a deficit in GSH induced either by GCLC shRNA (this study) or BSO 59 impairs oligodendrocyte maturation. These latter in vitro data are consistent with the impaired oligodendrocyte and myelination observed in GCLM-KO mice.…”

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

“…We showed that ephrinA5 colocalized with EGFR in certain regions on the plasma membrane. As phosphorylation by Fyn has been reported to regulate the E3 ligase activity of c-Cbl (Grossmann et al, 2004;Li et al, 2007), we hypothesize that the ephrinA5 reverse signaling triggered by EphA2-Fc would activate Fyn, which could phosphorylate c-Cbl, and facilitate c-Cbl-mediated EGFR degradation.…”

Casitas B-cell lymphoma (Cbl) proteins protect mammary epithelial cells from proteotoxicity of active c-Src accumulation

“…Additionally, we were also intrigued by the up-regulation of the heme oxygenase 1 (Hmox1) transcript in both datasets. Previously, Cbl was shown to be involved in responses to toxicants and oxidative stresses (30)(31)(32). Although we did not observe global up-regulation of oxidative stress-induced genes in the present datasets, because of these previous reports we decided to examine the oxidative stress pathway as well.…”