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PMID: 12077189 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The neural cell adhesion molecule L1 potentiates integrin-dependent cell migration to extracellular matrix proteins.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 12 ·2002-06-15 ·Pages 4918-31

Thelen K, Kedar V, Panicker AK, Schmid RS, Midkiff BR, Maness PF

Abstract

The L1 adhesion molecule regulates axon growth and is mutated in the X-linked mental retardation syndrome CRASH (acronym for corpus callosum agenesis, retardation, aphasia, spastic paraplegia, hydrocephalus). A novel role for L1 as a potentiator of neuronal cell migration to extracellular matrix proteins through beta1 integrins and intracellular signaling to mitogen-activated protein (MAP) kinase was identified. L1 potentiated haptotactic migration of B35 neuroblastoma cells toward fibronectin, vitronectin, and laminin through the signaling intermediates c-Src, phosphatidylinositol-3 kinase, and MAP kinase. L1 potentiated migration toward fibronectin through alpha5beta1 integrin in human embryonic kidney 293 cells and depended on determinants of L1 endocytosis: dynamin I, c-Src, and the AP2/clathrin binding site (Arg-Ser-Leu-Glu) in the neuronal splice form of L1. L1 clustering on the cell surface enhanced the internalization of activated beta1 integrins and L1 into distinct endocytic vesicles. L1-potentiated migration, enhancement of beta1 integrin endocytosis, and activation of MAP kinase were coordinately inhibited by mutation of an RGD sequence in the sixth immunoglobulin-like domain of L1. Moreover, three CRASH mutations in the L1 cytoplasmic domain (1194L, S1224L, Y1229H), two of which interfere with ankyrin association, inhibited L1-potentiated migration and MAP kinase activation. Function-blocking antibodies to L1 and beta1 integrin retarded the migration of 5-bromo-2'-deoxyuridine-labeled mouse cerebellar granule cells in slice cultures, underscoring the potential physiological relevance of these findings. These studies suggest that L1 functionally interacts with beta1 integrins to potentiate neuronal migration toward extracellular matrix proteins through endocytosis and MAP kinase signaling, and that impairment of this function by L1 cytoplasmic domain mutations may contribute to neurological deficits in CRASH.

MeSH Terms
Animals Antibodies/pharmacology Cell Line Cell Movement Cerebellum/cytology,physiology Endocytosis Extracellular Matrix Proteins/pharmacology Humans Integrin beta1/immunology,physiology Integrins/physiology Leukocyte L1 Antigen Complex MAP Kinase Signaling System Membrane Glycoproteins/chemistry,genetics,physiology Mice Mutation Neural Cell Adhesion Molecules/chemistry,genetics,physiology Neurons/physiology Oligopeptides/chemistry Protein Structure, Tertiary Rats Tumor Cells, Cultured
Chemicals
Antibodies Extracellular Matrix Proteins Integrin beta1 Integrins Leukocyte L1 Antigen Complex Membrane Glycoproteins Neural Cell Adhesion Molecules Oligopeptides arginyl-glycyl-aspartic acid
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Thelen Karsten
Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7260, USA.
Kedar Vishram
Panicker Anitha K
Schmid Ralf-Steffen
Midkiff Bentley R
Maness Patricia F
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2002-06-15
Pages
4918-31
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6757736
Subset
IM
Grants
NINDS NIH HHS · R01 NS026620 · United States
NICHD NIH HHS · HD35170 · United States
NINDS NIH HHS · NS26620 · United States
External Links
PubMed source PMC Full Text View journal details
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