Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins

The L1 adhesion molecule plays an important role in axon guidance and cell migration in the nervous system. L1 is also expressed by many human carcino mas. In addition to cell surface expression, the L1 ectodomain can be relea sed by a metalloproteinase, but the biological function of this process is unknown. Here we demonstrate that membrane-proximal cleavage of L1 can be d etected in tumors and in the developing mouse brain. The shedding of L1 inv olved a disintegrin and metalloproteinase (ADAM)10, as transfection with do minant-negative ADAM10 completely abolishes L1 release. L1-transfected CHO cells (L1-CHO) showed enhanced haptotactic migration on fibronectin and lam inin, which was blocked by anti-bodies to alphav beta5 and L1. Migration of LI-CHO cells, but not the basal migration of CHO cells, was blocked by a m etalloproteinase inhibitor, indicating a role for L1 shedding in the migrat ion process. CHO and metalloproteinase inhibited L1-CHO cells were stimulat ed to migrate by soluble L1-Fc protein. The induction of migration was bloc ked by alphav beta5-specific antibodies and required Arg-Gly-Asp sites in L 1. A 150-kD L1 fragment released by plasmin could also stimulate CHO cell m igration. We propose that ectodomain-released L1 promotes migration by auto crine/paracrine stimulation via alphav beta5. This regulatory loop could be relevant for migratory processes under physiological and pathophysiologica l conditions.