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PMID: 10818153 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 20 ·No. 11 ·2000-06-01 ·Pages 4177-88

Schmid RS, Pruitt WM, Maness PF

Abstract

The neural cell adhesion molecule L1 mediates the axon outgrowth, adhesion, and fasciculation necessary for proper development of synaptic connections. Mutations of human L1 cause an X-linked mental retardation syndrome termed CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia, and hydrocephalus), and L1 knock-out mice display defects in neuronal process extension resembling the CRASH phenotype. Little is known about the biochemical or cellular mechanism by which L1 performs neuronal functions. Here it is demonstrated that clustering of L1 with antibodies or L1 protein in rodent B35 neuroblastoma and cerebellar neuron cultures induced the phosphorylation/activation of the mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinases 1 and 2. MAPK activation was essential for L1-dependent neurite outgrowth, because chemical inhibitors [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one and 1,4-diamino-2, 3-dicyano-1,4-bis(2-aminophenylthio)butadiene] of the MAPK kinase MEK strongly suppressed neurite outgrowth by cerebellar neurons on L1. The nonreceptor tyrosine kinase pp60(c-src) was required for L1-triggered MAPK phosphorylation, as shown in src-minus cerebellar neurons and by expression of the kinase-inactive mutant Src(K295M) in B35 neuroblastoma cells. Phosphatidylinositol 3-kinase (PI3-kinase) and the small GTPase p21(rac) were identified as signaling intermediates to MAPK by phosphoinositide and Rac-GTP assays and expression of inhibitory mutants. Antibody-induced endocytosis of L1, visualized by immunofluorescence staining and confocal microscopy of B35 cells, was blocked by expression of kinase-inactive Src(K295M) and dominant-negative dynamin(K44A) but not by inhibitors of MEK or PI3-kinase. Dynamin(K44A) also inhibited L1 antibody-triggered MAPK phosphorylation. This study supports a model in which pp60(c-src) regulates dynamin-mediated endocytosis of L1 as an essential step in MAPK-dependent neurite outgrowth on an L1 substrate.

MeSH Terms
Animals Cell Nucleus/physiology,ultrastructure Cells, Cultured Cerebellum/cytology,physiology Cytoskeleton/genetics,physiology Endocytosis/physiology Growth Cones/physiology,ultrastructure Humans Intercellular Adhesion Molecule-1/physiology MAP Kinase Signaling System/physiology Mice Mitogen-Activated Protein Kinase 1/physiology Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases/physiology Neurites/physiology Neuroblastoma/enzymology,genetics,metabolism Phosphatidylinositol 3-Kinases/physiology Protein Serine-Threonine Kinases/physiology Proto-Oncogene Proteins pp60(c-src)/physiology p21-Activated Kinases
Chemicals
Intercellular Adhesion Molecule-1 Proto-Oncogene Proteins pp60(c-src) PAK3 protein, human Pak3 protein, mouse Protein Serine-Threonine Kinases p21-Activated Kinases Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Schmid R S
Department of Biochemistry, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7260, USA. srclab@med.unc.edu
Pruitt W M
Maness P 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
Email
srclab@med.unc.edu
Published
2000-06-01
Pages
4177-88
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6772629
Subset
IM
Grants
NINDS NIH HHS · R01 NS026620 · United States
NINDS NIH HHS · NS 26620 · United States
External Links
PubMed source PMC Full Text View journal details
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