title: The neural cell adhesion molecule (NCAM) associates with and signals through p21-activated kinase 1 (Pak1).
abstract: The Neural cell adhesion molecule (NCAM) plays an important role in regulation of nervous system development. To expand our understanding of the molecular mechanisms via which NCAM influences differentiation of neurons, we used a yeast two-hybrid screening to search for new binding partners of NCAM and identified p21-activated kinase 1 (Pak1). We show that NCAM interacts with Pak1 in growth cones of neurons. The autophosphorylation and activity of Pak1 were enhanced when isolated growth cones were incubated with NCAM function triggering antibodies, which mimic the interaction between NCAM and its extracellular ligands. The association of Pak1 with cell membranes, the efficiency of Pak1 binding to its activators, and Pak1 activity were inhibited in brains of NCAM-deficient mice. NCAM-dependent Pak1 activation was abolished after lipid raft disruption, suggesting that NCAM promotes Pak1 activation in the lipid raft environment. Phosphorylation of the downstream Pak1 effectors LIMK1 and cofilin was reduced in growth cones from NCAM-deficient neurons, which was accompanied by decreased levels of filamentous actin and inhibited filopodium mobility in the growth cones. Dominant-negative Pak1 inhibited and constitutively active Pak1 enhanced the ability of neurons to increase neurite outgrowth in response to the extracellular ligands of NCAM. Our combined observations thus indicate that NCAM activates Pak1 to drive actin polymerization to promote neuronal differentiation.
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Shen
authors.initials: S
authors.lastname: Li
authors.forename: Iryna
authors.initials: I
authors.lastname: Leshchyns'ka
authors.forename: Yana
authors.initials: Y
authors.lastname: Chernyshova
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sytnyk
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001923:Brain Chemistry; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D004247:DNA / Q000235:genetics; D005260:Female; D020439:Growth Cones / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D047468:Immunoprecipitation; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016501:Neurites / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics; D054462:p21-Activated Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: D000199:Actins; D000911:Antibodies, Monoclonal; D019006:Neural Cell Adhesion Molecules; D004247:DNA; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein