PathwayStep6170 PathwayStep6155 PathwayStep6156 PathwayStep6153 PathwayStep6154 PathwayStep6159 PathwayStep6157 PathwayStep6158 PathwayStep6151 PathwayStep6152 PathwayStep6150 PathwayStep6149 RAF/MAP kinase cascade NCAM1 interactions NCAM signaling for neurite out-growth Authored: Garapati, P V, 2009-02-24 10:31:41 Edited: Garapati, P V, 2009-02-24 10:31:41 Pubmed12587671 Pubmed12700044 Pubmed15153429 Pubmed15662836 Pubmed17975827 Pubmed18760361 Reactome Database ID Release 43375165 Reactome, http://www.reactome.org ReactomeREACT_18334 Reviewed: Maness, PF, Walmod, PS, 2009--0-5- The neural cell adhesion molecule, NCAM, is a member of the immunoglobulin (Ig) superfamily and is involved in a variety of cellular processes of importance for the formation and maintenance of the nervous system. The role of NCAM in neural differentiation and synaptic plasticity is presumed to depend on the modulation of intracellular signal transduction cascades. NCAM based signaling complexes can initiate downstream intracellular signals by at least two mechanisms: (1) activation of FGFR and (2) formation of intracellular signaling complexes by direct interaction with cytoplasmic interaction partners such as Fyn and FAK. Tyrosine kinases Fyn and FAK interact with NCAM and undergo phosphorylation and this transiently activates the MAPK, ERK 1 and 2, cAMP response element binding protein (CREB) and transcription factors ELK and NFkB. CREB activates transcription of genes which are important for axonal growth, survival, and synaptic plasticity in neurons.<br><br>NCAM1 mediated intracellular signal transduction is represented in the figure below. The Ig domains in NCAM1 are represented in orange ovals and Fn domains in green squares. The tyrosine residues susceptible to phosphorylation are represented in red circles and their positions are numbered. Phosphorylation is represented by red arrows and dephosphorylation by yellow. Ig, Immunoglobulin domain; Fn, Fibronectin domain; Fyn, Proto-oncogene tyrosine-protein kinase Fyn; FAK, focal adhesion kinase; RPTPalpha, Receptor-type tyrosine-protein phosphatase; Grb2, Growth factor receptor-bound protein 2; SOS, Son of sevenless homolog; Raf, RAF proto-oncogene serine/threonine-protein kinase; MEK, MAPK and ERK kinase; ERK, Extracellular signal-regulated kinase; MSK1, Mitogen and stress activated protein kinase 1; CREB, Cyclic AMP-responsive element-binding protein; CRE, cAMP response elements. PathwayStep3465 MSK1 activates CREB PathwayStep3473 ERK1/2 phosphorylates MSK1 SOS binds Grb2 bound to pFAK:NCAM1 NCAM1:pFAK:Grb2:Sos-mediated nucleotide exchange of Ras Recruitment of FAK to NCAM1:Fyn in lipid rafts Phosphorylation of FAK by Src kinase Dephosphorylation of NCAM1 bound pFyn Autophosphorylation of NCAM1 bound Fyn NCAM1 binds FGFR-1 Fyn binds NCAM1 NCAM1 cis-homophilic interaction NCAM1 trans-homophilic interaction Recruitment of Grb2 to pFAK:NCAM1 PathwayStep3857