Ethanol activates midkine and anaplastic lymphoma kinase signaling in neuroblastoma cells and in the brain

Alcohol engages signaling pathways in the brain. Midkine (MDK) is a neurotrophic factor that is over‐expressed in the prefrontal cortex of alcoholics.MDKand one of its receptors, anaplastic lymphoma kinase (ALK), also regulate behavioral responses to ethanol in mice. The goal of this study was to determine whetherMDKandALKexpression and signaling are activated by ethanol. We found that ethanol treatment of neuroblastoma cells increasedMDKandALKexpression. We also assessed activation ofALKby ethanol in cells and found thatALKandALK‐dependent extracellular signal‐regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) phosphorylation increased rapidly with ethanol exposure. Similarly, treatment of cells with recombinantMDKprotein increasedALK,ERKand STAT3 phosphorylation, suggesting that ethanol may utilizeMDKto activateALKsignaling. In support of this, transfection of cells withMDKsiRNAs attenuatedALKsignaling in response to ethanol. Ethanol also activatesERKsignaling in the brain. We found that inhibition ofALKor knockout ofMDKattenuated ethanol‐inducedERKphosphorylation in mouse amygdala. These results demonstrate that ethanol engagesMDKandALKsignaling, which has important consequences for alcohol‐induced neurotoxicity and the regulation of behaviors related to alcohol abuse. image We propose that ethanol (a) increases transcription of the anaplastic lymphoma kinase (ALK) and midkine (MDK) genes and (b) rapidly activates extracellular signal‐regulated kinase (pERK1/2) and signal transducer and activator of transcription 3 (pSTAT3) through MDK and ALK. Activation of ALK and MDK signaling by ethanol may alter behavioral responses to ethanol with implications for the development of alcohol use disorders.