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¹ Tumor Immunology Program, G0100, German Cancer Research Center, D-69120 Heidelberg, Germany
² Department of Pathology, Kaplan Hospital, Rehovot 76100, Israel
³ Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106
⁴ Institute of Biochemistry, University of Mainz, D-55128 Mainz, Germany

Address correspondence to Peter Altevogt, Tumor Immunology Program, G0100, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Tel.: 49-6221-423-714. Fax: 49-6221-423-702. E-mail: p.altevogt{at}dkfz-heidelberg.de

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 carcinomas. In addition to cell surface expression, the L1 ectodomain can be released by a metalloproteinase, but the biological function of this process is unknown. Here we demonstrate that membrane-proximal cleavage of L1 can be detected in tumors and in the developing mouse brain. The shedding of L1 involved a disintegrin and metalloproteinase (ADAM)10, as transfection with dominant-negative ADAM10 completely abolishes L1 release. L1-transfected CHO cells (L1-CHO) showed enhanced haptotactic migration on fibronectin and laminin, which was blocked by antibodies to vß5 and L1. Migration of L1-CHO cells, but not the basal migration of CHO cells, was blocked by a metalloproteinase inhibitor, indicating a role for L1 shedding in the migration process. CHO and metalloproteinase-inhibited L1-CHO cells were stimulated to migrate by soluble L1-Fc protein. The induction of migration was blocked by vß5-specific antibodies and required Arg-Gly-Asp sites in L1. A 150-kD L1 fragment released by plasmin could also stimulate CHO cell migration. We propose that ectodomain-released L1 promotes migration by autocrine/paracrine stimulation via vß5. This regulatory loop could be relevant for migratory processes under physiological and pathophysiological conditions.

Key Words: L1; shedding; ADAM10; cell migration; integrins

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