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The Journal of Neuroscience, June 15, 2002, 22(12):4918-4931
The Neural Cell Adhesion Molecule L1 Potentiates
Integrin-Dependent Cell Migration to Extracellular Matrix Proteins
Karsten
Thelen*,
Vishram
Kedar*,
Anitha K.
Panicker*,
Ralf-Steffen
Schmid,
Bentley R.
Midkiff, and
Patricia F.
Maness
Department of Biochemistry and Biophysics, University of North
Carolina School of Medicine, Chapel Hill, North Carolina 27599-7260
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  1 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  51
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 1 integrins and L1 into distinct endocytic vesicles.
L1-potentiated migration, enhancement of 1 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 1 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
1 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.
Key words:
L1; integrin; cell migration; endocytosis; MAP kinase; mental retardation
*
K.T., V.K., and A.K.P. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/22124918-14$05.00/0
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