Signal transduction pathways implicated in neural recognition molecule L1 triggered neuroprotection and...

The signal transduction pathways involved in adhesion molecule L1-triggered neuritogenesis and neuroprotection were investigated using the extracellular domain of mouse or human L1 in fusion with the Fc portion of human immunoglobulin G or L1 purified from mouse brain by affinity chromatography. Substrate L1-triggered neuritogenesis and neuroprotection depended on distinct but also overlapping signal transduction pathways and on the expression of L1 at the neuronal cell surface. PI3 kinase inhibitors, Src family kinase inhibitors as well as mitogen-activated protein kinase kinase inhibitors reduced both L1-triggered neuritogenesis and neuroprotection. In contrast, fibroblast growth factor receptor inhibitors, a protein kinase A inhibitor, and an inhibitor of cAMP-mediated signal transduction pathways, blocked neuritogenesis, but did not affect L1-triggered neuroprotection. Proteolytic cleavage of L1 or its interaction partners is necessary for both L1-mediated neuritogensis and neuroprotection. Furthermore, L1-triggered neuroprotection was found to be associated with increased phosphorylation of extracellular signal-regulated kinases 1/2, Akt and Bad, and inhibition of caspases. These observations suggest possibilities of differentially targeting signal transduction pathways for L1-dependent neuritogenesis and neuroprotection.