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PMID: 11706054 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of cell biology ·Vol. 155 ·No. 4 ·2001-11-12 ·Pages 661-73

Mechtersheimer S, Gutwein P, Agmon-Levin N, Stoeck A, Oleszewski M, Riedle S, Postina R, Fahrenholz F, Fogel M, Lemmon V, Altevogt P

Abstract

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 alpha v beta 5 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 alpha v beta 5-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 alpha v beta 5. This regulatory loop could be relevant for migratory processes under physiological and pathophysiological conditions.

MeSH Terms
Amyloid Precursor Protein Secretases Animals Antibodies, Monoclonal/immunology Aspartic Acid Endopeptidases Autocrine Communication Binding Sites Biological Transport Brain/embryology,metabolism CHO Cells Cell Membrane/metabolism Cell Movement/physiology Cricetinae Cytoplasm/metabolism Endopeptidases/metabolism Fibrinolysin/metabolism Gene Expression Humans Integrins/immunology,metabolism Leukocyte L1 Antigen Complex Membrane Glycoproteins/antagonists & inhibitors,genetics,metabolism Mice Neural Cell Adhesion Molecules/antagonists & inhibitors,genetics,metabolism Oligopeptides/metabolism Peptide Fragments/metabolism Receptors, Vitronectin Solubility Tumor Cells, Cultured
Chemicals
Antibodies, Monoclonal Integrins Leukocyte L1 Antigen Complex Membrane Glycoproteins Neural Cell Adhesion Molecules Oligopeptides Peptide Fragments Receptors, Vitronectin integrin alphaVbeta5 arginyl-glycyl-aspartic acid Amyloid Precursor Protein Secretases Endopeptidases Fibrinolysin Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Mechtersheimer S
Tumor Immunology Program, G0100, German Cancer Research Center, D-69120 Heidelberg, Germany.
Gutwein P
Agmon-Levin N
Stoeck A
Oleszewski M
Riedle S
Postina R
Fahrenholz F
Fogel M
Lemmon V
Altevogt P
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200101099
Published
2001-11-12
Epub
2001-00-12
Pages
661-73
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2198870
Subset
IM
Grants
NEI NIH HHS · R01 EY005285 · United States
NEI NIH HHS · EY05285 · United States
NEI NIH HHS · R01 EY005285-23 · United States
NICHD NIH HHS · R01 HD039884-06 · United States
NICHD NIH HHS · R01 HD039884 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1083/jcb.200101099 PMC Full Text View journal details
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