NCAM signaling for neurite out-growth (Homo sapiens)

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2, 4-6, 11...95, 12, 131, 8165, 1297, 14, 1812, 19Spectrin alpha chain NCAM1 complexed with pFyn-Y420 Multiple phosphorylated FAK bound to NCAMpFyn NCAM1 complexed with pFyn-Y420 GDNF family ligands NCAM1 cis-homodimer T-type VDCC Spectrin alpha chain NCAM1FGFR-1 Spectrin heterodimer L-type VDCC Collagen type IX NCAM1 cis-homodimer NCAM1 complexed with Fyn p21 RASGTP Spectrin heterodimer NCAM1NCAM1 trans-homotetramer NCAMpFyn-Y420 NCAM1NCAM1 trans-homotetramer Collagen alpha-1Spectrin alpha chain NCAM-1Major prion protein NCAM1 complexed with pFyn-Y420 NCAM1 cis-homodimer Spectrin beta chain NCAM1GFRalpha-1 Spectrin heterodimer Collagen type IX Collagen alpha-1NCAM1NCAM1 trans-homotetramer NCAM1NCAM1 trans-homotetramer Spectrin heterodimer pFAKGrb2Sos Spectrin heterodimer NCAM1NCAM1 trans-homotetramer pFAK Type IV collagen Spectrin beta chain NCAM1 complexed with pFyn-Y420 Polysialylated NCAM p21 RAS NCAM1 cis-homodimer Spectrin alpha chain Collagens NCAM1GFRalpha-1 NCAM1 cis-homodimer NCAM1NCAM1 trans-homotetramer NCAMpFyn-Y420 Spectrin beta chain NCAM1 complexed with pFyn-Y420 T- and L-type VDCC Collagen alpha-2Spectrin alpha chain NCAM-1Neurocan Collagens Grb2pFAK bound to NCAM1pFyn Golgi lumenSpectrin beta chain Spectrin beta chain NCAM-1Collagen complex Collagen alpha-2Spectrin beta chain NCAM-1ATP FGFR1c homodimer Tropocollagen type VI p21 RASGDP NCAM1 cis-homodimer FGFR1c homodimer Tropocollagen type VI Collagen alpha-1cytosolCollagen alpha-1NCAM1 cis-homodimer NCAM complexed with Fyn p21 RAS FynNCAM1RPTP-alpha Collagen alpha-3NCAM1 cis-homodimer Type IV collagen NCAM1NCAM1 trans-homotetramer Spectrin alpha chain pFAKGrb2 NCAM-1Agrin NCAMpFyn-Y420 NCAM1GFRalpha-1GDNF Grb2SospFAK bound to NCAM1pFyn nucleoplasmSpectrin heterodimer NCAM1 cis-homodimer NCAM1 cis-homodimer Spectrin alpha chain NCAM1NCAM1 trans-homotetramer NCAM1 cis-homodimer Spectrin heterodimer Spectrin beta chain NCAMpFyn-Y420 Collagen alpha-3NCAM1T- and L-type VDCC NCAM1-Contactin-2 NCAMpFyn-Y420 NCAM1NCAM1 trans-homotetramer 3x4Hyp-COL6A1 AGRNCOL4A4SPTBN5 NRAS 3x4Hyp-GalHyl-COL6A1 SPTBN4 SPTBN5 SPTBN4 p-Y531-FYNCACNA1C 3x4Hyp-GalHyl-COL6A1 CNTN2RPS6KA5NCAM-1ATPATPFGFR1c PTPRA NCAM-1NeurocanSPTAN1 CACNB3 p-Y531-FYNNCAN CACNA1S NCAM1p21 RASGTPATPCollagensNCAM1SPTBN1 COL6A2 6xN-linked glycan core-NCAM1COL6A2 3x4Hyp-3Hyp-5Hyl-COL6A2 PSPN SPTAN1 NCAM1 complexed with Fynp-S133-CREB1PRNPGDP Polysialic acidGRB2-1GTPFynNCAM1RPTP-alphaSPTBN2SPTA13x4Hyp-3Hyp-5Hyl-COL6A1 CACNA1G 3x4Hyp-3Hyp-COL6A2 AGRNGFRalphaCOL9A1 CACNB4 NCAM1 cis-homodimerSPTBN5 pFAK SPTA1GDPSPTBN2GDNF PTPRA COL4A16xN-linked glycan core-NCAM1CACNB1 FGFR1c homodimerATP3x4Hyp-GlcGalHyl-COL6A1 NCAM1NCAM1GFRalpha-1GDNFFYNSPTBN4 GalHyl-COL6A2 CACNA1H SPTBN4 NCAM1SPTBN2p-6Y-PTK2 CACNA1D p-6Y-PTK2 SPTBN2NCAM1GRB2-1 NRAS SPTB GTP 3x4Hyp-COL6A2 SOS1 p-Y420-FYNNCAM1COL4A2GalHyl-COL6A1 COL4A55Hyl-COL6A1 NCAM1CACNB2 NCAM1 complexed with pFyn-Y420NCAM-1Major prion proteinFYN3x4Hyp-5Hyl-COL6A2 NCAM-1Collagen complexFGFR1c NCAM13x4Hyp-COL6A1 COL9A3 ARTN SPTBN1 SPTBN1 SPTBN4 NCAM1NCAM1 trans-homotetramerSPTB ADP3x4Hyp-3Hyp-GalHyl-COL6A1 GlcGalHyl-COL6A1 PRNP SPTBN2COL9A2 SPTA1COL9A1 PTPRA NCAM1FGFR-13x4Hyp-GlcGalHyl-COL6A2 SPTA1p-Y397-PTK2 NCAM1GFRalpha-1SPTA13x4Hyp-3Hyp-COL6A2 COL9A3 ADPp-Y420-FYNGalHyl-COL6A2 5Hyl-COL6A2 3x4Hyp-3Hyp-5Hyl-COL6A1 3x4Hyp-GlcGalHyl-COL6A1 Grb2SospFAK bound to NCAM1pFynCOL9A2 SPTB p-6Y-PTK2 SPTAN1 COL4A43x4Hyp-5Hyl-COL6A2 COL6A1 ATPSPTA1SPTB GlcGalHyl-COL6A2 SPTA1Spectrin heterodimer3x4Hyp-3Hyp-COL6A1 ATP NCAM1COL4A2SOS1HRASGalHyl-COL6A1 NCAM1T- and L-type VDCCNCAM1SPTBN4 COL4A3GlcGalHyl-COL6A2 COL6A1 p-S212,S360,S376,T581-RPS6KA53x4Hyp-3Hyp-5Hyl-COL6A2 3x4Hyp-GalHyl-COL6A2 p-Y420-FYNATP3x4Hyp-3Hyp-COL6A1 p21 RASGDP5Hyl-COL6A1 COL4A5NCAM1SPTBN4 COL4A3p-Y420-FYNCACNA1I SPTBN1 SPTB CREB13x4Hyp-GalHyl-COL6A2 SRC-13x4Hyp-GlcGalHyl-COL6A2 KRASADPPTPRA PiSPTBN1 SPTAN1 Multiple phosphorylated FAK bound to NCAMpFynHRASGlcGalHyl-COL6A1 PTPRA p-Y420-FYNPTK2ADPSPTBN5 ATPSPTAN1 NCAM1COL4A1SPTBN23x4Hyp-3Hyp-GalHyl-COL6A2 GDNF family ligands SPTBN1 NCAM-1AgrinRAF/MAP kinase cascadeNCAM1NCAM1-Contactin-2NCAM1NCAM1SPTBN5 3x4Hyp-3Hyp-GlcGalHyl-COL6A1 NCAM1SPTBN1 ADPSPTB GRB2-1 5Hyl-COL6A2 3x4Hyp-3Hyp-GalHyl-COL6A1 PTPRA Polysialylated NCAMNCAM1NCAM1alpha 2-8 polysialyltransferases3x4Hyp-3Hyp-GlcGalHyl-COL6A1 NCAM1SPTB SPTAN1 CNTN2 3x4Hyp-3Hyp-GalHyl-COL6A2 SPTBN2NCANGrb2pFAK bound to NCAM1pFyn3x4Hyp-5Hyl-COL6A1 3x4Hyp-3Hyp-GlcGalHyl-COL6A2 T- and L-type VDCCNRTN 3x4Hyp-3Hyp-GlcGalHyl-COL6A2 PTPRASPTBN5 3x4Hyp-COL6A2 NCAM1SPTBN5 Phospho-ERK dimer3x4Hyp-5Hyl-COL6A1 NCAM1KRASSPTAN1 10103, 1710


Description

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.

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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=375165

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114681view16:15, 25 January 2021ReactomeTeamReactome version 75
113128view11:19, 2 November 2020ReactomeTeamReactome version 74
112360view15:29, 9 October 2020ReactomeTeamReactome version 73
101261view11:15, 1 November 2018ReactomeTeamreactome version 66
100799view20:43, 31 October 2018ReactomeTeamreactome version 65
100341view19:20, 31 October 2018ReactomeTeamreactome version 64
99886view16:03, 31 October 2018ReactomeTeamreactome version 63
99443view14:37, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99113view12:40, 31 October 2018ReactomeTeamreactome version 62
93875view13:42, 16 August 2017ReactomeTeamreactome version 61
93442view11:23, 9 August 2017ReactomeTeamreactome version 61
88031view13:34, 25 July 2016RyanmillerOntology Term : 'signaling pathway pertinent to the brain and nervous system' added !
88028view13:33, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86533view09:20, 11 July 2016ReactomeTeamreactome version 56
83314view10:45, 18 November 2015ReactomeTeamVersion54
81453view12:59, 21 August 2015ReactomeTeamVersion53
76927view08:19, 17 July 2014ReactomeTeamFixed remaining interactions
76632view12:00, 16 July 2014ReactomeTeamFixed remaining interactions
75963view10:02, 11 June 2014ReactomeTeamRe-fixing comment source
75665view10:57, 10 June 2014ReactomeTeamReactome 48 Update
75020view13:53, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74664view08:43, 30 April 2014ReactomeTeamReactome46
42084view21:55, 4 March 2011MaintBotAutomatic update
39892view05:55, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
3x4Hyp-3Hyp-5Hyl-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-5Hyl-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GalHyl-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GalHyl-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GlcGalHyl-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
3x4Hyp-3Hyp-GlcGalHyl-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
3x4Hyp-5Hyl-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
3x4Hyp-5Hyl-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
3x4Hyp-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
3x4Hyp-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
3x4Hyp-GalHyl-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
3x4Hyp-GalHyl-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
3x4Hyp-GlcGalHyl-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
3x4Hyp-GlcGalHyl-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
5Hyl-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
5Hyl-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
6xN-linked glycan core-NCAM1ProteinP13591 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AGRNProteinO00468 (Uniprot-TrEMBL)
ARTN ProteinQ5T4W7 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CACNA1C ProteinQ13936 (Uniprot-TrEMBL)
CACNA1D ProteinQ01668 (Uniprot-TrEMBL)
CACNA1G ProteinO43497 (Uniprot-TrEMBL)
CACNA1H ProteinO95180 (Uniprot-TrEMBL)
CACNA1I ProteinQ9P0X4 (Uniprot-TrEMBL)
CACNA1S ProteinQ13698 (Uniprot-TrEMBL)
CACNB1 ProteinQ02641 (Uniprot-TrEMBL)
CACNB2 ProteinQ08289 (Uniprot-TrEMBL)
CACNB3 ProteinP54284 (Uniprot-TrEMBL)
CACNB4 ProteinO00305 (Uniprot-TrEMBL)
CNTN2 ProteinQ02246 (Uniprot-TrEMBL)
CNTN2ProteinQ02246 (Uniprot-TrEMBL)
COL4A1ProteinP02462 (Uniprot-TrEMBL)
COL4A2ProteinP08572 (Uniprot-TrEMBL)
COL4A3ProteinQ01955 (Uniprot-TrEMBL)
COL4A4ProteinP53420 (Uniprot-TrEMBL)
COL4A5ProteinP29400 (Uniprot-TrEMBL)
COL6A1 ProteinP12109 (Uniprot-TrEMBL)
COL6A2 ProteinP12110 (Uniprot-TrEMBL)
COL9A1 ProteinP20849 (Uniprot-TrEMBL)
COL9A2 ProteinQ14055 (Uniprot-TrEMBL)
COL9A3 ProteinQ14050 (Uniprot-TrEMBL)
CREB1ProteinP16220 (Uniprot-TrEMBL)
CollagensComplexREACT_18161 (Reactome)
FGFR1c ProteinP11362-1 (Uniprot-TrEMBL)
FGFR1c homodimerComplexREACT_9800 (Reactome)
FYNProteinP06241 (Uniprot-TrEMBL)
Fyn

NCAM1

RPTP-alpha		ComplexREACT_18571 (Reactome)
GDNF ProteinP39905 (Uniprot-TrEMBL)
GDNF family ligands ProteinREACT_20000 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GFRalphaProteinREACT_19467 (Reactome)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
GalHyl-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
GalHyl-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
GlcGalHyl-COL6A1 ProteinP12109 (Uniprot-TrEMBL)
GlcGalHyl-COL6A2 ProteinP12110 (Uniprot-TrEMBL)
Grb2

Sos pFAK bound to NCAM1

pFyn		ComplexREACT_18839 (Reactome)
Grb2

pFAK bound to NCAM1

pFyn		ComplexREACT_18783 (Reactome)
HRASProteinP01112 (Uniprot-TrEMBL)
KRASProteinP01116 (Uniprot-TrEMBL)
Multiple phosphorylated FAK bound to NCAM pFynComplexREACT_18768 (Reactome)
NCAM-1 ATPComplexREACT_18582 (Reactome)
NCAM-1 AgrinComplexREACT_19071 (Reactome)
NCAM-1 Collagen complexComplexREACT_18833 (Reactome)
NCAM-1 Major prion proteinComplexREACT_18842 (Reactome)
NCAM-1 NeurocanComplexREACT_18891 (Reactome)
NCAM1 FGFR-1ComplexREACT_18900 (Reactome)
NCAM1

GFRalpha-1

GDNF		ComplexREACT_18598 (Reactome)
NCAM1 GFRalpha-1ComplexREACT_18445 (Reactome)
NCAM1 NCAM1 trans-homotetramerComplexREACT_18931 (Reactome)
NCAM1 T- and L-type VDCCComplexREACT_21777 (Reactome)
NCAM1 cis-homodimerComplexREACT_19070 (Reactome)
NCAM1 complexed with FynComplexREACT_18556 (Reactome)
NCAM1 complexed with pFyn-Y420ComplexREACT_18470 (Reactome)
NCAM1-Contactin-2ComplexREACT_19032 (Reactome)
NCAM1ProteinP13591 (Uniprot-TrEMBL)
NCAN ProteinO14594 (Uniprot-TrEMBL)
NCANProteinO14594 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
NRTN ProteinQ99748 (Uniprot-TrEMBL)
PRNP ProteinP04156 (Uniprot-TrEMBL)
PRNPProteinP04156 (Uniprot-TrEMBL)
PSPN ProteinO60542 (Uniprot-TrEMBL)
PTK2ProteinQ05397 (Uniprot-TrEMBL)
PTPRA ProteinP18433 (Uniprot-TrEMBL)
PTPRAProteinP18433 (Uniprot-TrEMBL)
Phospho-ERK dimerREACT_12827 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
Polysialic acidREACT_18892 (Reactome)
Polysialylated NCAMComplexREACT_18914 (Reactome)
RAF/MAP kinase cascadePathwayWP2735 (WikiPathways) The MAP kinase cascade describes a sequence of phosphorylation events involving serine/threonine-specific protein kinases. Used by various signal transduction pathways, this cascade constitutes a common 'module' in the transmission of an extracellular signal into the nucleus.
RPS6KA5ProteinO75582 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SOS1ProteinQ07889 (Uniprot-TrEMBL)
SPTA1ProteinP02549 (Uniprot-TrEMBL)
SPTAN1 ProteinQ13813 (Uniprot-TrEMBL)
SPTB ProteinP11277 (Uniprot-TrEMBL)
SPTBN1 ProteinQ01082 (Uniprot-TrEMBL)
SPTBN2ProteinO15020 (Uniprot-TrEMBL)
SPTBN4 ProteinQ9H254 (Uniprot-TrEMBL)
SPTBN5 ProteinQ9NRC6 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
Spectrin heterodimerComplexREACT_19000 (Reactome) Spectrin is a protein found at the intracellular surface of the plasma membrane in many cell types. In association with other proteins particularly protein 4.1 and ankyrin it forms hexagonal or pentagonal structures that act as a plasma membrane scaffold for other membrane structures and as an attachment point for cytoskeletal proteins such as actin. The erythrocyte forms of spectrin are the best studied (and not exclusievely expressed in erthrocytes).
T- and L-type VDCCProteinREACT_21538 (Reactome)
alpha 2-8 polysialyltransferasesREACT_18945 (Reactome)
p-6Y-PTK2 ProteinQ05397 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S212,S360,S376,T581-RPS6KA5ProteinO75582 (Uniprot-TrEMBL)
p-Y397-PTK2 ProteinQ05397 (Uniprot-TrEMBL)
p-Y420-FYNProteinP06241 (Uniprot-TrEMBL)
p-Y531-FYNProteinP06241 (Uniprot-TrEMBL)
p21 RAS GDPComplexREACT_2657 (Reactome)
p21 RAS GTPComplexREACT_4782 (Reactome)
pFAK ComplexREACT_18498 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
6xN-linked glycan core-NCAM1REACT_18324 (Reactome)
ADPArrowREACT_12576 (Reactome)
ADPArrowREACT_12631 (Reactome)
ADPArrowREACT_18333 (Reactome)
ADPArrowREACT_18343 (Reactome)
ADPArrowREACT_18385 (Reactome)
AGRNREACT_18305 (Reactome)
ATPREACT_12576 (Reactome)
ATPREACT_12631 (Reactome)
ATPREACT_18264 (Reactome)
ATPREACT_18333 (Reactome)
ATPREACT_18343 (Reactome)
ATPREACT_18385 (Reactome)
CNTN2REACT_18282 (Reactome)
CREB1REACT_12631 (Reactome)
CollagensREACT_18390 (Reactome)
FGFR1c homodimerREACT_18337 (Reactome)
FYNREACT_18343 (Reactome)
Fyn

NCAM1

RPTP-alpha		ArrowREACT_18389 (Reactome)
Fyn

NCAM1

RPTP-alpha		REACT_18343 (Reactome)
GDNF family ligands REACT_18328 (Reactome)
GDPArrowREACT_18366 (Reactome)
GFRalphaREACT_18304 (Reactome)
GRB2-1REACT_18375 (Reactome)
GTPREACT_18366 (Reactome)
Grb2

Sos pFAK bound to NCAM1

pFyn		REACT_18366 (Reactome)
Grb2

pFAK bound to NCAM1

pFyn		REACT_18259 (Reactome)
Multiple phosphorylated FAK bound to NCAM pFynArrowREACT_18385 (Reactome)
Multiple phosphorylated FAK bound to NCAM pFynREACT_18375 (Reactome)
NCAM-1 ATPTBarREACT_18337 (Reactome)
NCAM1 GFRalpha-1REACT_18328 (Reactome)
NCAM1 NCAM1 trans-homotetramerREACT_18353 (Reactome)
NCAM1 NCAM1 trans-homotetramerREACT_21373 (Reactome)
NCAM1 cis-homodimerREACT_18337 (Reactome)
NCAM1 complexed with FynREACT_18389 (Reactome)
NCAM1 complexed with pFyn-Y420ArrowREACT_18343 (Reactome)
NCAM1 complexed with pFyn-Y420REACT_18333 (Reactome)
NCAM1REACT_18264 (Reactome)
NCAM1REACT_18282 (Reactome)
NCAM1REACT_18304 (Reactome)
NCAM1REACT_18305 (Reactome)
NCAM1REACT_18390 (Reactome)
NCAM1REACT_18406 (Reactome)
NCAM1REACT_18427 (Reactome)
NCANREACT_18427 (Reactome)
PRNPREACT_18406 (Reactome)
PTK2REACT_18333 (Reactome)
PTPRAREACT_18389 (Reactome)
Phospho-ERK dimerREACT_12576 (Reactome)
PiArrowREACT_18389 (Reactome)
Polysialic acidREACT_18324 (Reactome)
REACT_12576 (Reactome) MSK1 (Ribosomal protein S6 kinase alpha-5) is a serine/threonine kinase that is localised in the nucleus. It contains two protein kinase domains in a single polypeptide. It can be activated 5-fold by ERK1/2 through phosphorylation at four key residues.
REACT_12631 (Reactome) MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB).
REACT_18259 (Reactome) Guanine nucleotide releasing factor Sos associates with FAK bound Grb2 to activate Ras and initiate Ras-MAPK signaling. This interaction occurs between the carboxy terminal domain of SOS and the Src homology 3 (SH3) domains of GRB2.
REACT_18264 (Reactome) NCAM1 has been demonstrated to possess (Ca++ or Mg++) dependant ATP hydrolyzing activity. ATP can bind to NCAM directly and that NCAM can act as an ecto-ATPase hydrolyzing around 1000 molecules of ATP/minute. Binding of ATP to NCAM1 inhibits cellular aggregation and neurite outgrowth induced by NCAM1-FGFR binding. The NCAM binding site to ATP overlaps with the site of NCAM-FGFR interaction, and ATP is capable of disrupting NCAM-FGFR binding.
REACT_18267 (Reactome) NCAM1 located on the cell membrane can participate in parallel cis and antiparallel trans-homophilic interactions. The cis-interaction is mediated by reciprocal IgI-IgII interactions: the IgI domain of one NCAM1 molecule interacts with the IgII domain of a second.
REACT_18271 (Reactome) Antiparallel NCAM interactions involve trans-interactions of NCAM molecules on opposed cell membranes. Based on structural and functional studies a 'double zipper' model has been proposed to describe these interactions. The first model - the 'flat zipper'- formed between NCAM1 cis-dimers from one cell surface interacting in trans through IgII-IgIII contacts with NCAM1 cis-dimers from another cell surface. The second model - the 'compact zipper'- is formed between NCAM1 cis-dimers from one cell surface interacting in trans through IgI-IgIII and IgII-IgII contacts with cis-dimers from another cell surface.

Abrogation of cis-dimerization inhibits NCAM mediated neurite outgrowth, and cis-dimerization of NCAM1 may be a necessary prerequisite for subsequent trans-interactions.

REACT_18282 (Reactome) NCAM1 binds with high affinity to the neuronal IgSF receptor, contactin-2/TAG-1/axonin-1.
REACT_18304 (Reactome) GFRalpha receptors GFRalpha1 and possibly also GFRalpha2 and GFRalpha4 subunit of the GDNF (glial cell line-derived neurotrophic factor) receptor interact in cis with NCAM and functions as a coreceptor for GDNF in the absence of RET. The NCAM1-GFRalpha1 interaction down regulates NCAM1-mediated cell adhesion and promotes GDNF-NCAM1 binding.
REACT_18305 (Reactome) Agrin, a Heparin Sulfate Proteoglycan (HSPG), plays a role in synaptogenesis and axonal growth. It interacts with NCAM1 both via NCAM's heparin binding domain in the IgII domain and through polysialic acid on the IgV domain.
REACT_18324 (Reactome) NCAM in the developing brain is highly polysialylated and is referred as the embryonic form of NCAM. Polysialic acid is a developmentally regulated, anti-adhesive glycan with a linear homopolymer of alpha2,8-linked sialic acid units. They are mainly attached to the fifth and sixth N-glycosylation sites of the fifth Ig-like domain of NCAM. Polysialylation of NCAM is catalyzed by two polysialyltransferases, ST8Sia II (STX) and ST8Sia IV (PST), which belong to the family of six genes encoding alpha2,8-sialyltransferases. These enzymes add polysialic acid to NCAM N-glycans until it reaches a certain size (up to 200 sialic acid residues), where neither enzyme can interact with polysialylated N-glycans, and the polymerization of sialic acid is terminated.
Due to the structure with its chemical nature, polysialic acid can attenuate the interaction of NCAM with NCAM and other molecules in the same membrane (cis-interaction) or in another cell membrane (trans-interaction). During axonal growth the presence of polysialic acid along axons seems to prevent inappropriate synapse formation.
REACT_18328 (Reactome) NCAM was identified as an alternative signaling receptor for GDNF family ligands (GFLs). The GFLs is a small group of soluble neurotrophic growth factors involved in neuronal survival, neurite growth and differentiation. Four members are known in the family including GDNF, Neurturin (NTN), Persephin (PSP), and Artemin (ART). NCAM, in collaboration with GFR? receptors, function as a signaling receptor for these GFLs. Signaling downstream of GDNF binding to the NCAM-GFRalpha1 complex activates Fyn-FAK-MAPK signaling pathway and mediates long-range intercellular communication.
REACT_18333 (Reactome) Fyn activation leads to the recruitment and activation of the non-receptor tyrosine kinase FAK. Once recruited to Fyn, FAK undergoes autophosphorylation on tyrosine 397. This tyrosine allows the binding of SH2 domain containing proteins.
REACT_18337 (Reactome) FGFR is one of the heterophilic interactors of NCAM. The FG loop region of the second Fn3 module of NCAM binds to Ig domains 2 and 3 of FGFR. The FGFR binding site to NCAM overlaps with the site of NCAM-ATP interaction, and ATP is capable of disrupting NCAM-FGFR binding and signaling.
The interaction of NCAM activates FGFR and NCAM might merely mimic FGF's in FGFR stimulation, but there is a difference in the activation pattern induced by NCAM and FGF-2. NCAM activated FGFR stimulates neurite outgrowth by stimulating PLCgamma and DAG lipase leading to generation of arachidonic acid.
REACT_18343 (Reactome) The Tyr420 residue located in the activation loop of Fyn is responsible for its enzymatic activity. Once the Tyr531 in its negative regulatory site is dephosphorylated by RPTPalpha, Fyn undergoes autophosphorylation on Tyr420 for its maximum activity.
REACT_18353 (Reactome) Fyn constitutively associates with the 140 kD isoform of NCAM1 in the plasma membrane, probably indirectly. Fyn is attached to the lipid raft membrane compartment via palmitoylation and is inactivated by tyrosine phosphorylation (Y531) within its C-terminal regulatory region. Fyn kinase has two well-known phosphorylation sites which affect its activity in opposite ways. The phosphorylation of Tyr531 located in the C-terminus of the protein inhibits the Fyn kinase activity, due to the binding of this tyrosine residue to the SH2 domain of the protein, which stabilizes its catalytically inactive conformation.
REACT_18366 (Reactome) The guanine nucleotide exchange factor SOS interacts with GRB2 bound to phosphorylated FAK bound to NCAM. Upon formation of this complex, SOS activates Ras by promoting GDP release and GTP binding.
REACT_18375 (Reactome) Phosphorylated tyrosine 925 in the FAT domain of FADK1 creates a docking site for the SH2 domain of GRB2 and recruits the GRB2/SOS complex. FADK1 may use this mechanism to activate Ras and the MAP kinase pathway.
REACT_18385 (Reactome) Phosphorylation of Tyr397 in FAK triggers the phosphorylation of other tyrosine residues (Tyr407, Tyr576, Tyr577, Tyr861 and Tyr925) in a Src-dependent manner. The initial phosphorylation of FAK at Tyr397 is thought to create a high-affinity binding site for SH2 domains, enabling formation of a signalling complex between FAK and members of the Src-family kinases. Tyr-576 and Tyr-577 are located in the central catalytic domain and their phosphorylation is required for the maximum kinase activity of FAK. The tyrosine phosphorylation of these residues is likely to be mediated by Src (or other members of the src family).
REACT_18389 (Reactome) The homophilic NCAM1:NCAM1 interaction redistributes these molecules and leads to the formation of clusters within lipid rafts. Spectrin, an NCAM1 binding cytoskeletal protein, colocalizes with NCAM1 and codistribute to lipid rafts. Spectrin associates with RPTP-alpha, linking it to the cytoplasmic NCAM1 domain and causing its coredistribution to lipid rafts on NCAM1 clustering. The receptor tyrosine phosphatase RPTP-alpha is an activator of all kinases of the Src family, including Fyn kinase.

The interaction of RPTP-alpha and the SH2 domain of Fyn induces an interaction of Fyn Tyr531 with the D1 domain of RPTP-alpha. This induces dephosphorylation of Tyr531 and activates Fyn.

REACT_18390 (Reactome) NCAM1 interacts with several extracellular matrix proteins. NCAM1 has been reported to bind collagens I-IV and IX.
REACT_18406 (Reactome) Prion protein (PrP) is a GPI-anchored protein predominately localized in lipid rafts. NCAM1 is one of the membrane localized proteins that binds PrP. PrP is though to bind NCAM1 at the IgV, F3I and/or F3II domains in an interaction not involving the various carbohydrate moieties of NCAM1. The functional relevance of this interaction is unknown, but may be related to the effects of PrP on activation and proliferation of haemopoietic cells expressing NCAM1.
REACT_18427 (Reactome) NCAM1 bind all major components of neurocan (N-terminal, central and C-terminal regions as well as CS chains), a brain-specific chondroitin sulfate proteoglycan. This molecule interferes with homophilic NCAM1 interactions and inhibits neuronal adhesion and neurite outgrowth.
REACT_21373 (Reactome) NCAM1 associates with T- and L-type voltage-dependent Ca+2 channels (VDCC) in growthcones at the sites of NCAM1 clustering. This interaction leads to the NCAM-dependent Ca+2 influx to the cell.
RPS6KA5REACT_12576 (Reactome)
SOS1REACT_18259 (Reactome)
SRC-1REACT_18385 (Reactome)
Spectrin heterodimerREACT_18389 (Reactome)
T- and L-type VDCCREACT_21373 (Reactome)
alpha 2-8 polysialyltransferasesREACT_18324 (Reactome)
p-S133-CREB1ArrowREACT_12631 (Reactome)
p-S212,S360,S376,T581-RPS6KA5ArrowREACT_12576 (Reactome)
p-S212,S360,S376,T581-RPS6KA5REACT_12631 (Reactome)
p-Y531-FYNREACT_18353 (Reactome)
p21 RAS GDPREACT_18366 (Reactome)
p21 RAS GTPArrowREACT_18366 (Reactome)
pFAK ArrowREACT_18333 (Reactome)
pFAK REACT_18385 (Reactome)
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