NCAM signaling for neurite out-growth (Homo sapiens)

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2, 3, 6, 28, 29, 3113, 28882422, 2613, 2012, 13, 287, 9, 21nucleoplasmGolgi lumencytosolGalHyl-COL6A1 SPTBN1 3x4Hyp-COL6A2 GDPSPTBN1 CNTN2 NCAM1 GDNF family ligands(GFLs)Type IV collagen NCAM-1:ATPNCAM1 FGFR1c ATPNCAM1 NCAM1 KRAS NCAM1 alpha2-8polysialyltransferasesSPTB Collagen type II fibril SPTA1 Collagen type V fibril 5Hyl-COL6A2 p-Y420-FYN COL9A2 CREB1SPTBN5 SPTAN1 SPTBN1 AGRN(30-2045) NRTN SPTBN4 GDNF 3x4Hyp-3Hyp-GlcGalHyl-COL6A1 3x4Hyp-3Hyp-5Hyl-COL6A1 SOS13x4Hyp-3Hyp-GalHyl-COL6A2 3x4Hyp-GalHyl-COL6A2 NCAM1:T- and L-typeVDCCSPTB SPTB ATPSPTB 6xN-linked glycancore-NCAM1SPTB SPTBN4 SPTBN1 SPTAN1 GFRA1 PRNP PTPRA GlcGalHyl-COL6A1 SPTAN1 3x4Hyp-5Hyl-COL6A2 HRAS Collagen alpha-5(VI) chains 3x4Hyp-5Hyl-COL6A1 NCAN3x4Hyp-GlcGalHyl-COL6A2 Polysialic acidSPTBN4 3x4Hyp-3Hyp-GalHyl-COL6A1 3x4Hyp-GalHyl-COL6A2 PSPN ARTN GFRA4 KRAS p-Y531-FYN FGFR1c L-type VDCC 3x4Hyp-3Hyp-5Hyl-COL6A1 Collagen type III fibril SPTA1 HRAS GFRA4 Collagen type III fibril NCAM1 NCAN GDNF GalHyl-COL6A1 NCAM1-Contactin-2Collagen type II fibril NCAM-1:CollagencomplexSPTBN2 T- and L-type VDCC3x4Hyp-GlcGalHyl-COL6A2 SPTAN1 p-Y420-FYN 3x4Hyp-GalHyl-COL6A1 PiCOL9A1 Collagen alpha-3(VI) chains GFRA1 PTPRA NRTN pFAK (391) bound toNCAM1:pFynCOL6A2 p-Y420-FYN GFRA1 GRB2-1CollagensADPSOS1 NCAN3x4Hyp-COL6A2 ATPPRNPNCAM1:GFRalpha-1:GDNFFGFR1c Grb2:Sos:pFAK boundto NCAM1:pFynp-T202,Y204-MAPK3 NCAM-1:NeurocanGFRA2 PSPN p-T,Y MAPK dimersL-type VDCC GFRA1 NRAS NCAM1 NCAM1:NCAM1trans-homotetramer3x4Hyp-5Hyl-COL6A1 AGRN(30-2045)Collagen alpha-6(VI) chains Multiplephosphorylated FAKbound to NCAM:pFynPSPN SPTB 3x4Hyp-3Hyp-COL6A1 SPTAN1 p-Y420-FYN PTPRA ADPp-6Y-PTK2 p21 RAS:GDPPTPRA NCAM1 p-Y531-FYNSOS1 NCAM1 6xN-linked glycan core-NCAM1 ARTN COL9A3 3x4Hyp-COL6A1 NCAM1 cis-homodimerNRAS NCAM1 complexed withpFyn-Y420SPTA1 5Hyl-COL6A1 NCAM1 complexed withFyn3x4Hyp-5Hyl-COL6A2 3x4Hyp-3Hyp-COL6A2 ATPSPTBN4 p-Y420-FYN NCAM-1:Major prionproteinCOL9A2 SPTBN5 Grb2:Sos:pFAK boundto NCAM1:pFynCOL9A1 SPTBN2 p-T185,Y187-MAPK1 SPTBN2 GTPST8SIA2 SPTBN2 T-type VDCC p-S133-CREB1ST8SIA4 SPTA1 SPTBN2 3x4Hyp-3Hyp-5Hyl-COL6A2 SPTA:SPTB3x4Hyp-COL6A1 SPTAN1 GlcGalHyl-COL6A1 NCAM1 ADPRPS6KA5T-type VDCC GFRA2 Polysialylated NCAMFYN COL9A3 PTK2COL6A2 SPTBN5 SPTBN2 SPTBN1 NCAM1 NCAM1 3x4Hyp-3Hyp-GalHyl-COL6A1 COL6A1 3x4Hyp-3Hyp-GlcGalHyl-COL6A1 ADPp-T,Y MAPK dimersp-S212,S360,S376,T581-RPS6KA5ATPNCAM-1:NeurocanGFRA2 Polysialic acid SPTBN5 SPTBN1 Grb2:pFAK bound toNCAM1:pFynGRB2-1 p-6Y-PTK2 NCAM13x4Hyp-3Hyp-5Hyl-COL6A2 3x4Hyp-GalHyl-COL6A1 3x4Hyp-GlcGalHyl-COL6A1 3x4Hyp-3Hyp-COL6A1 NCAM1 CNTN2Collagen alpha-6(VI) chains 3x4Hyp-COL6A2 GDP NCAM1 GTP ATPNCAM-1:AgrinGalHyl-COL6A2 RAF/MAP kinasecascadeNCAM1 5Hyl-COL6A2 3x4Hyp-3Hyp-COL6A2 3x4Hyp-3Hyp-GalHyl-COL6A2 NCAM1 Collagen type V fibril ADPSPTBN5 SRC-1PTPRANCAM1:GFRalpha-1:GDNFNCAM1:FGFR-1GFRalphaPRNPCollagen alpha-3(VI) chains L-type VDCC p21 RAS:GTPATP NCAM1 SPTA1 p-6Y-PTK2 NCAM1SPTBN4 SPTBN2 GalHyl-COL6A2 5Hyl-COL6A1 SPTB 3x4Hyp-3Hyp-GlcGalHyl-COL6A2 Collagen alpha-5(VI) chains SPTBN1 SPTAN1 NCAM1 NCAM1:GFRalpha-1SPTBN5 p-Y397-PTK2 GFRA2 SPTA1 GRB2-1 PTPRA Fyn:NCAM1:RPTP-alpha441, 5, 10, 14, 16...11, 15, 27411, 15, 27 >


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. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 375165
Reactome version: 66
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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  1. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
  2. Povlsen GK, Ditlevsen DK, Berezin V, Bock E.; ''Intracellular signaling by the neural cell adhesion molecule.''; PubMed Europe PMC Scholia
  3. Walmod PS, Kolkova K, Berezin V, Bock E.; ''Zippers make signals: NCAM-mediated molecular interactions and signal transduction.''; PubMed Europe PMC Scholia
  4. Relou IA, Bax LA, van Rijn HJ, Akkerman JW.; ''Site-specific phosphorylation of platelet focal adhesion kinase by low-density lipoprotein.''; PubMed Europe PMC Scholia
  5. McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMed Europe PMC Scholia
  6. Kiryushko D, Berezin V, Bock E.; ''Regulators of neurite outgrowth: role of cell adhesion molecules.''; PubMed Europe PMC Scholia
  7. Angata K, Fukuda M.; ''Polysialyltransferases: major players in polysialic acid synthesis on the neural cell adhesion molecule.''; PubMed Europe PMC Scholia
  8. Deak M, Clifton AD, Lucocq LM, Alessi DR.; ''Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB.''; PubMed Europe PMC Scholia
  9. Rutishauser U.; ''Polysialic acid in the plasticity of the developing and adult vertebrate nervous system.''; PubMed Europe PMC Scholia
  10. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
  11. Chen L, Miyamura N, Ninomiya Y, Handa JT.; ''Distribution of the collagen IV isoforms in human Bruch's membrane.''; PubMed Europe PMC Scholia
  12. Schlaepfer DD, Hanks SK, Hunter T, van der Geer P.; ''Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase.''; PubMed Europe PMC Scholia
  13. Probstmeier R, Kühn K, Schachner M.; ''Binding properties of the neural cell adhesion molecule to different components of the extracellular matrix.''; PubMed Europe PMC Scholia
  14. Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMed Europe PMC Scholia
  15. Fukuda K, Hori H, Utani A, Burbelo PD, Yamada Y.; ''Formation of recombinant triple-helical [alpha 1(IV)]2 alpha 2(IV) collagen molecules in CHO cells.''; PubMed Europe PMC Scholia
  16. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
  17. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
  18. Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMed Europe PMC Scholia
  19. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia
  20. ''''; PubMed Europe PMC Scholia
  21. Weinhold B, Seidenfaden R, Röckle I, Mühlenhoff M, Schertzinger F, Conzelmann S, Marth JD, Gerardy-Schahn R, Hildebrandt H.; ''Genetic ablation of polysialic acid causes severe neurodevelopmental defects rescued by deletion of the neural cell adhesion molecule.''; PubMed Europe PMC Scholia
  22. Dzhandzhugazyan K, Bock E.; ''Demonstration of (Ca(2+)-Mg2+)-ATPase activity of the neural cell adhesion molecule.''; PubMed Europe PMC Scholia
  23. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed Europe PMC Scholia
  24. Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMed Europe PMC Scholia
  25. Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMed Europe PMC Scholia
  26. Dzhandzhugazyan K, Bock E.; ''Demonstration of an extracellular ATP-binding site in NCAM: functional implications of nucleotide binding.''; PubMed Europe PMC Scholia
  27. Sado Y, Kagawa M, Naito I, Ueki Y, Seki T, Momota R, Oohashi T, Ninomiya Y.; ''Organization and expression of basement membrane collagen IV genes and their roles in human disorders.''; PubMed Europe PMC Scholia
  28. Panicker AK, Buhusi M, Thelen K, Maness PF.; ''Cellular signalling mechanisms of neural cell adhesion molecules.''; PubMed Europe PMC Scholia
  29. Ditlevsen DK, Povlsen GK, Berezin V, Bock E.; ''NCAM-induced intracellular signaling revisited.''; PubMed Europe PMC Scholia
  30. Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMed Europe PMC Scholia
  31. Schmid RS, Maness PF.; ''L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth.''; PubMed Europe PMC Scholia
  32. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
  33. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed Europe PMC Scholia
  34. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia


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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


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)
6xN-linked glycan core-NCAM1 ProteinP13591 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AGRN(30-2045) ProteinO00468 (Uniprot-TrEMBL)
AGRN(30-2045)ProteinO00468 (Uniprot-TrEMBL)
ARTN ProteinQ5T4W7 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CNTN2 ProteinQ02246 (Uniprot-TrEMBL)
CNTN2ProteinQ02246 (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)
Collagen alpha-3(VI) chains R-HSA-2192698 (Reactome)
Collagen alpha-5(VI) chains R-HSA-2127458 (Reactome)
Collagen alpha-6(VI) chains R-HSA-2127492 (Reactome)
Collagen type II fibril R-HSA-1474209 (Reactome)
Collagen type III fibril R-HSA-1474212 (Reactome)
Collagen type V fibril R-HSA-1609685 (Reactome)
CollagensComplexR-HSA-375078 (Reactome)
FGFR1c ProteinP11362-1 (Uniprot-TrEMBL)
FGFR1c homodimerComplexR-HSA-190222 (Reactome)
FYN ProteinP06241 (Uniprot-TrEMBL)
Fyn:NCAM1:RPTP-alphaComplexR-HSA-391845 (Reactome)
GDNF ProteinP39905 (Uniprot-TrEMBL)
GDNF family ligands (GFLs)ComplexR-HSA-434920 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GFRA1 ProteinP56159 (Uniprot-TrEMBL)
GFRA2 ProteinO00451 (Uniprot-TrEMBL)
GFRA4 ProteinQ9GZZ7 (Uniprot-TrEMBL)
GFRalphaComplexR-HSA-434924 (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:pFynComplexR-HSA-392045 (Reactome)
Grb2:pFAK bound to NCAM1:pFynComplexR-HSA-392047 (Reactome)
HRAS ProteinP01112 (Uniprot-TrEMBL)
KRAS ProteinP01116 (Uniprot-TrEMBL)
L-type VDCC R-HSA-525825 (Reactome)

phosphorylated FAK

bound to NCAM:pFyn
ComplexR-HSA-391848 (Reactome)
NCAM-1:ATPComplexR-HSA-375093 (Reactome)
NCAM-1:AgrinComplexR-HSA-375096 (Reactome)
NCAM-1:Collagen complexComplexR-HSA-375098 (Reactome)
NCAM-1:Major prion proteinComplexR-HSA-375105 (Reactome)
NCAM-1:NeurocanComplexR-HSA-375100 (Reactome)
NCAM1 ProteinP13591 (Uniprot-TrEMBL)
NCAM1 cis-homodimerComplexR-HSA-190988 (Reactome)
NCAM1 complexed with FynComplexR-HSA-391847 (Reactome)
NCAM1 complexed with pFyn-Y420ComplexR-HSA-391842 (Reactome)
NCAM1-Contactin-2ComplexR-HSA-375108 (Reactome)
NCAM1:FGFR-1ComplexR-HSA-419028 (Reactome)
NCAM1:GFRalpha-1:GDNFComplexR-HSA-375111 (Reactome)
NCAM1:GFRalpha-1ComplexR-HSA-375101 (Reactome)
NCAM1:NCAM1 trans-homotetramerComplexR-HSA-375103 (Reactome)
NCAM1:T- and L-type VDCCComplexR-HSA-525828 (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)
PiMetaboliteCHEBI:18367 (ChEBI)
Polysialic acid R-HSA-422427 (Reactome)
Polysialic acidR-HSA-422427 (Reactome)
Polysialylated NCAMComplexR-HSA-422441 (Reactome)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RPS6KA5ProteinO75582 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SOS1ProteinQ07889 (Uniprot-TrEMBL)
SPTA1 ProteinP02549 (Uniprot-TrEMBL)
SPTA:SPTBComplexR-HSA-391839 (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).
SPTAN1 ProteinQ13813 (Uniprot-TrEMBL)
SPTB ProteinP11277 (Uniprot-TrEMBL)
SPTBN1 ProteinQ01082 (Uniprot-TrEMBL)
SPTBN2 ProteinO15020 (Uniprot-TrEMBL)
SPTBN4 ProteinQ9H254 (Uniprot-TrEMBL)
SPTBN5 ProteinQ9NRC6 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
ST8SIA2 ProteinQ92186 (Uniprot-TrEMBL)
ST8SIA4 ProteinQ92187 (Uniprot-TrEMBL)
T- and L-type VDCCComplexR-HSA-525824 (Reactome)
T-type VDCC R-HSA-525821 (Reactome)
Type IV collagen R-HSA-215993 (Reactome)


ComplexR-HSA-422438 (Reactome)
p-6Y-PTK2 ProteinQ05397 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-S212,S360,S376,T581-RPS6KA5ProteinO75582 (Uniprot-TrEMBL)
p-T,Y MAPK dimersComplexR-HSA-198701 (Reactome)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-Y397-PTK2 ProteinQ05397 (Uniprot-TrEMBL)
p-Y420-FYN ProteinP06241 (Uniprot-TrEMBL)
p-Y531-FYN ProteinP06241 (Uniprot-TrEMBL)
p-Y531-FYNProteinP06241 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)
pFAK (391) bound to NCAM1:pFynComplexR-HSA-391841 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
6xN-linked glycan core-NCAM1R-HSA-422454 (Reactome)
ADPArrowR-HSA-198756 (Reactome)
ADPArrowR-HSA-199935 (Reactome)
ADPArrowR-HSA-391865 (Reactome)
ADPArrowR-HSA-391866 (Reactome)
ADPArrowR-HSA-391871 (Reactome)
AGRN(30-2045)R-HSA-375155 (Reactome)
ATPR-HSA-198756 (Reactome)
ATPR-HSA-199935 (Reactome)
ATPR-HSA-375160 (Reactome)
ATPR-HSA-391865 (Reactome)
ATPR-HSA-391866 (Reactome)
ATPR-HSA-391871 (Reactome)
CNTN2R-HSA-375157 (Reactome)
CREB1R-HSA-199935 (Reactome)
CollagensR-HSA-375151 (Reactome)
FGFR1c homodimerR-HSA-419033 (Reactome)
Fyn:NCAM1:RPTP-alphaArrowR-HSA-391868 (Reactome)
Fyn:NCAM1:RPTP-alphaR-HSA-391871 (Reactome)
Fyn:NCAM1:RPTP-alphamim-catalysisR-HSA-391871 (Reactome)
GDNF family ligands (GFLs)R-HSA-375144 (Reactome)
GDPArrowR-HSA-392054 (Reactome)
GFRalphaR-HSA-375149 (Reactome)
GRB2-1R-HSA-392051 (Reactome)
GTPR-HSA-392054 (Reactome)
Grb2:Sos:pFAK bound to NCAM1:pFynArrowR-HSA-392053 (Reactome)
Grb2:Sos:pFAK bound to NCAM1:pFynmim-catalysisR-HSA-392054 (Reactome)
Grb2:pFAK bound to NCAM1:pFynArrowR-HSA-392051 (Reactome)
Grb2:pFAK bound to NCAM1:pFynR-HSA-392053 (Reactome)

phosphorylated FAK

bound to NCAM:pFyn
ArrowR-HSA-391866 (Reactome)

phosphorylated FAK

bound to NCAM:pFyn
R-HSA-392051 (Reactome)
NCAM-1:ATPArrowR-HSA-375160 (Reactome)
NCAM-1:ATPTBarR-HSA-419033 (Reactome)
NCAM-1:AgrinArrowR-HSA-375155 (Reactome)
NCAM-1:Collagen complexArrowR-HSA-375151 (Reactome)
NCAM-1:Major prion proteinArrowR-HSA-375154 (Reactome)
NCAM-1:NeurocanArrowR-HSA-375148 (Reactome)
NCAM1 cis-homodimerArrowR-HSA-391872 (Reactome)
NCAM1 cis-homodimerR-HSA-375161 (Reactome)
NCAM1 cis-homodimerR-HSA-419033 (Reactome)
NCAM1 complexed with FynArrowR-HSA-391867 (Reactome)
NCAM1 complexed with FynR-HSA-391868 (Reactome)
NCAM1 complexed with pFyn-Y420ArrowR-HSA-391871 (Reactome)
NCAM1 complexed with pFyn-Y420R-HSA-391865 (Reactome)
NCAM1-Contactin-2ArrowR-HSA-375157 (Reactome)
NCAM1:FGFR-1ArrowR-HSA-419033 (Reactome)
NCAM1:GFRalpha-1:GDNFArrowR-HSA-375144 (Reactome)
NCAM1:GFRalpha-1ArrowR-HSA-375149 (Reactome)
NCAM1:GFRalpha-1R-HSA-375144 (Reactome)
NCAM1:NCAM1 trans-homotetramerArrowR-HSA-375161 (Reactome)
NCAM1:NCAM1 trans-homotetramerR-HSA-391867 (Reactome)
NCAM1:NCAM1 trans-homotetramerR-HSA-525833 (Reactome)
NCAM1:T- and L-type VDCCArrowR-HSA-525833 (Reactome)
NCAM1R-HSA-375148 (Reactome)
NCAM1R-HSA-375149 (Reactome)
NCAM1R-HSA-375151 (Reactome)
NCAM1R-HSA-375154 (Reactome)
NCAM1R-HSA-375155 (Reactome)
NCAM1R-HSA-375157 (Reactome)
NCAM1R-HSA-375160 (Reactome)
NCAM1R-HSA-391872 (Reactome)
NCANR-HSA-375148 (Reactome)
PRNPR-HSA-375154 (Reactome)
PTK2R-HSA-391865 (Reactome)
PTK2mim-catalysisR-HSA-391865 (Reactome)
PTPRAR-HSA-391868 (Reactome)
PTPRAmim-catalysisR-HSA-391868 (Reactome)
PiArrowR-HSA-391868 (Reactome)
Polysialic acidR-HSA-422454 (Reactome)
Polysialylated NCAMArrowR-HSA-422454 (Reactome)
R-HSA-198756 (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.
R-HSA-199935 (Reactome) MSK1 is required for the mitogen-induced phosphorylation of the transcription factor, cAMP response element-binding protein (CREB).
R-HSA-375144 (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.
R-HSA-375148 (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.
R-HSA-375149 (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.
R-HSA-375151 (Reactome) NCAM1 interacts with several extracellular matrix proteins. NCAM1 has been reported to bind collagens I-IV and IX.
R-HSA-375154 (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.
R-HSA-375155 (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.
R-HSA-375157 (Reactome) NCAM1 binds with high affinity to the neuronal IgSF receptor, contactin-2/TAG-1/axonin-1.
R-HSA-375160 (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.
R-HSA-375161 (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.

R-HSA-391865 (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.
R-HSA-391866 (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).
R-HSA-391867 (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.
R-HSA-391868 (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.

R-HSA-391871 (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.
R-HSA-391872 (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.
R-HSA-392051 (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.
R-HSA-392053 (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.
R-HSA-392054 (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.
R-HSA-419033 (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.
R-HSA-422454 (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.
R-HSA-525833 (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.
RPS6KA5R-HSA-198756 (Reactome)
SOS1R-HSA-392053 (Reactome)
SPTA:SPTBR-HSA-391868 (Reactome)
SRC-1mim-catalysisR-HSA-391866 (Reactome)
T- and L-type VDCCR-HSA-525833 (Reactome)


mim-catalysisR-HSA-422454 (Reactome)
p-S133-CREB1ArrowR-HSA-199935 (Reactome)
p-S212,S360,S376,T581-RPS6KA5ArrowR-HSA-198756 (Reactome)
p-S212,S360,S376,T581-RPS6KA5mim-catalysisR-HSA-199935 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-198756 (Reactome)
p-Y531-FYNR-HSA-391867 (Reactome)
p21 RAS:GDPR-HSA-392054 (Reactome)
p21 RAS:GTPArrowR-HSA-392054 (Reactome)
pFAK (391) bound to NCAM1:pFynArrowR-HSA-391865 (Reactome)
pFAK (391) bound to NCAM1:pFynR-HSA-391866 (Reactome)
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