The glycoprotein L1 mediates axon guidance and cell migration in the nervous system. Mechtersheimer et al. find that L1 in newborn mouse brain and in certain tumor cells is cleaved. The soluble fragment promotes migration over several substrates, and transfection of CHO cells with an L1 construct enhances migration.
Based on inhibition studies and experiments with mutants, the authors suggest that the metalloproteinase ADAM10 cleaves L1, and the L1 fragment then binds integrins on the same or a nearby cell. Signaling downstream of the integrin probably acts as a general stimulus for migration. ADAM10 can also cleave certain growth factors, thus activating their signaling pathways, which may converge with the L1/ integrin pathway. As L1 and ADAM10 are widely expressed, the temporal and spatial regulation of L1 cleavage may involve as yet uncharacterized molecules. ▪