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

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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. Discovering general principles underlying the effects of toxicant exposure on biological systems is one of the central challenges of toxicological research. We have discovered a previously unrecognized regulatory pathway on which chemically diverse toxicants converge, at environmentally relevant exposure levels, to disrupt the function of progenitor cells of the developing central nervous system. We found that the ability of low levels of methylmercury, lead, and paraquat to make progenitor cells more oxidized causes activation of an enzyme called Fyn kinase. Activated Fyn then activates another enzyme (c-Cbl) that modifies specific proteins—receptors that are required for cell division and survival—to initiate the proteins' degradation. By enhancing degradation of these receptors, their downstream signaling functions are repressed. Analysis of developmental exposure to methylmercury provided evidence that this same pathway is activated in vivo by environmentally relevant toxicant levels. The remarkable sensitivity of progenitor cells to low levels of toxicant exposure, and the discovery of the redox/Fyn/c-Cbl pathway as a mechanism by which small increases in oxidative status can markedly alter cell function, provide a novel and specific means by which exposure to chemically diverse toxicants might perturb normal development. In addition, the principles revealed in our studies appear likely to have broad applicability in understanding the regulation of cell function by alterations in redox balance, regardless of how they might be generated.