Ethanol inhibits L1 cell adhesion molecule activation of mitogen‐activated protein kinases

Abstract

Inhibition of the functions of L1 cell adhesion molecule (L1) by ethanol has been implicated in the pathogenesis of the neurodevelopmental aspects of the fetal alcohol syndrome (FAS). Ethanol at pharmacological concentrations has been shown to inhibit L1-mediated neurite outgrowth of rat post-natal day 6 cerebellar granule cells (CGN). Extracellular signal-related kinases (ERK) 1/2 activation occurs following L1 clustering. Reduction in phosphoERK1/2 by inhibition of mitogen-activated protein kinase kinase (MEK) reduces neurite outgrowth of cerebellar neurons. Here, we examine the effects of ethanol on L1 activation of ERK1/2, and whether this activation occurs via activation of fibroblast growth factor receptor 1 (FGFR1). Ethanol at 25 mM markedly inhibited ERK1/2 activation by both clustering L1 with cross-linked monoclonal antibodies, or by L1-Fc chimeric proteins. Clustering L1 with subsequent ERK1/2 activation did not result in tyrosine phosphorylation of the FGFR1. In addition, inhibition of FGFR1 tyrosine kinase blocked basic fibroblast growth factor (bFGF) activation of ERK1/2, but did not affect activation of ERK1/2 by clustered L1. We conclude that ethanol disrupts the signaling pathway between L1 clustering and ERK1/2 activation, and that this occurs independently of the FGFR1 pathway in cerebellar granule cells.

The cytoplasmic part of L1-CAM controls growth and gene expression in human tumors that is reversed by therapeutic antibodies

“…The mAbs to L1 could drastically reduce Erk and Src activation. It is interesting to note that in neuronal cells, L1 crosslinking with antibodies led to Erk activation (Schaefer et al, 1999;Tang et al, 2006), whereas in carcinoma cells the opposite is observed. In SKOV3ip cells that were used before as a therapy model in nude mice (Arlt et al, 2006;Knogler et al, 2007), the treatment with L1-mAbs was accompanied by changes in the expression pattern of Erk-regulated genes.…”

Cerebellar Granule Cell Migration and the Effects of Alcohol

“…The reduction of MAPK/Erk activity may be involved in the alcohol-induced impairment of granule cell migration. This is because the reduction of phosphorylated Erk1 and Erk2 by inhibition of MAPK kinase inhibits neurite outgrowth in cerebellar granule cells [138] . Moreover, PKC and PKA alter the phosphorylation of Erk [139] .…”

Mechanisms of ethanol-induced degeneration in the developing, mature, and aging cerebellum

“…In addition, ethanol has been shown to affect, e.g., several signal transduction pathways (218,219,220), neuronal adhesion molecules (221,222), and extracellular matrix proteins (171), which may contribute to the ethanol-induced pathology of the developing, mature and/or aging cerebellum. Several important questions, however, remain to be answered in future studies on ethanol-induced cerebellar degeneration: (i) What is the relative impact of each of the described mechanisms in the cerebellum vs. in other CNS areas sensitive to ethanol-induced pathology (e.g., frontal cortex, hippocampus, basal cholinergic neurons)?…”