PMID- 10818153
OWN - NLM
STAT- MEDLINE
DCOM- 20000615
LR  - 20220316
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 20
IP  - 11
DP  - 2000 Jun 1
TI  - A MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires 
      Src-dependent endocytosis.
PG  - 4177-88
AB  - 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.
FAU - Schmid, R S
AU  - Schmid RS
AD  - Department of Biochemistry, School of Medicine, University of North Carolina, 
      Chapel Hill, North Carolina 27599-7260, USA. srclab@med.unc.edu
FAU - Pruitt, W M
AU  - Pruitt WM
FAU - Maness, P F
AU  - Maness PF
LA  - eng
GR  - R01 NS026620/NS/NINDS NIH HHS/United States
GR  - NS 26620/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins pp60(c-src))
RN  - EC 2.7.11.1 (PAK3 protein, human)
RN  - EC 2.7.11.1 (Pak3 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (p21-Activated Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Cell Nucleus/physiology/ultrastructure
MH  - Cells, Cultured
MH  - Cerebellum/cytology/*physiology
MH  - Cytoskeleton/genetics/physiology
MH  - Endocytosis/physiology
MH  - Growth Cones/physiology/ultrastructure
MH  - Humans
MH  - Intercellular Adhesion Molecule-1/*physiology
MH  - MAP Kinase Signaling System/*physiology
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 1/physiology
MH  - Mitogen-Activated Protein Kinase 3
MH  - Mitogen-Activated Protein Kinases/physiology
MH  - Neurites/*physiology
MH  - Neuroblastoma/enzymology/genetics/metabolism
MH  - Phosphatidylinositol 3-Kinases/*physiology
MH  - Protein Serine-Threonine Kinases/*physiology
MH  - Proto-Oncogene Proteins pp60(c-src)/*physiology
MH  - p21-Activated Kinases
PMC - PMC6772629
EDAT- 2000/05/20 00:00
MHDA- 2000/06/17 00:00
PMCR- 2000/12/01
CRDT- 2000/05/20 00:00
PHST- 2000/05/20 00:00 [pubmed]
PHST- 2000/06/17 00:00 [medline]
PHST- 2000/05/20 00:00 [entrez]
PHST- 2000/12/01 00:00 [pmc-release]
AID - 20/11/4177 [pii]
AID - 4210 [pii]
AID - 10.1523/JNEUROSCI.20-11-04177.2000 [doi]
PST - ppublish
SO  - J Neurosci. 2000 Jun 1;20(11):4177-88. doi: 10.1523/JNEUROSCI.20-11-04177.2000.