TY - JOUR
T1 - Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins
AU - Mechtersheimer, Sabine
AU - Gutwein, Paul
AU - Agmon-Levin, Nancy
AU - Stoeck, Alexander
AU - Oleszewski, Matthias
AU - Riedle, Svenja
AU - Postina, Rolf
AU - Fahrenholz, Falk
AU - Fogel, Mina
AU - Lemmon, Vance
AU - Altevogt, Peter
PY - 2001/11/12
Y1 - 2001/11/12
N2 - 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 anti-bodies to αvβ5 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 metalloproteinaseinhibited L1-CHO cells were stimulated to migrate by soluble L1-Fc protein. The induction of migration was blocked by αvβ5-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 αvβ5. This regulatory loop could be relevant for migratory processes under physiological and pathophysiological conditions.
AB - 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 anti-bodies to αvβ5 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 metalloproteinaseinhibited L1-CHO cells were stimulated to migrate by soluble L1-Fc protein. The induction of migration was blocked by αvβ5-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 αvβ5. This regulatory loop could be relevant for migratory processes under physiological and pathophysiological conditions.
KW - ADAM10
KW - Cell migration
KW - Integrins
KW - L1
KW - Shedding
UR - http://www.scopus.com/inward/record.url?scp=84924172827&partnerID=8YFLogxK
U2 - 10.1083/jcb.200101099
DO - 10.1083/jcb.200101099
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C2 - 11706054
AN - SCOPUS:84924172827
SN - 0021-9525
VL - 155
SP - 661
EP - 673
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 4
ER -
