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

o PL SBIOLOGY ChemicallyDiverseToxicantsConverge onFynandc-CbltoDisruptPrecursorCell Function Zaibo Li,Tiefei Dong, Chris Pro¨schel, Mark Noble* DepartmentofBiomedicalGenetics,UniversityofRochesterMedicalCenter,Rochester,NewYork,UnitedStatesofAmerica Identificationofcommonmechanisticprinciplesthatshedlightontheactionofthemanychemicallydiversetoxicants towhichweareexposedisofcentralimportanceinunderstandinghowtoxicantsdisruptnormalcellularfunctionand 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 strikingconvergence,atenvironmentallyrelevantexposurelevels,onpathway-specificdisruptionofreceptortyrosine 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 activationofthec-Cbl ubiquitinligase.Fyn/c-Cblpathwayactivation bythese pro-oxidativechangescausesspecific reductions,invitroandinvivo,inlevelsofthec-Cbltargetplatelet-derivedgrowthfactorreceptor-aandotherc-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 pathwayofoxidant-mediatedFyn/c-Cblactivationasasharedmechanismofactionofchemicallydiversetoxicantsat environmentallyrelevantlevels,andasameansbywhichincreasedoxidativestatusmaydisruptmitogenicsignaling. These results provide one of a small number of general mechanistic principles in toxicology, and the only such principleintegratingtoxicology,precursorcellbiology,redoxbiology,andsignalingpathwayanalysisinapredictive framework