The Neural Cell Adhesion Molecule NCAM2/OCAM/RNCAM, a Close Relative to NCAM

  • Nikolaj Kulahin
  • Peter S. WalmodEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 663)


Cell adhesion molecules (CAMs) constitute a large class of plasma membrane-anchored proteins that mediate attachment between neighboring cells and between cells and the surrounding extracellular matrix (ECM). However, CAMs are more than simple mediators of cell adhesion. The neural cell adhesion molecule (NCAM) is a well characterized, ubiquitously expressed CAM that is highly expressed in the nervous system. In addition to mediating cell adhesion, NCAM participates in a multitude of cellular events, including survival, migration, and differentiation of cells, outgrowth of neurites, and formation and plasticity of synapses. NCAM shares an overall sequence identity of ∼44% with the neural cell adhesion molecule 2 (NCAM2), a protein also known as olfactory cell adhesion molecule (OCAM) and Rb-8 neural cell adhesion molecule (RNCAM), and the region-for-region sequence homology between the two proteins suggests that they are transcribed from paralogous genes. However, very little is known about the function of NCAM2, although it originally was described more than 20 years ago. In this review, we summarize the known properties and functions of NCAM2 and describe some of the differences and similarities between NCAM and NCAM2.


NCAM NCAM2 Neural cell adhesion molecule OCAM Olfactory system RNCAM 

List of Abbreviations


Adenosine 5′-triphosphate


Cell adhesion molecule


Close homolog of L1


Central nervous system


Extracellular matrix


Extracellular signal-regulated kinase


Focal adhesion kinase


Fibroblast growth factor receptor


Fibronectin type 3






Myelin-associated glycoprotein


Melanoma cell adhesion molecule


Mitral and/or tufted cell


Neural cell adhesion molecule


NADPH: Quinone oxidoreductase1


Olfactory bulb


Olfactory cell adhesion molecule


Olfactory epithelium


Odorant receptor


Olfactory sensory neuron


Polysialic acid


Rb-8 neural cell adhesion molecule


Receptor protein tyrosine phosphatase


Src-homology 3


Signal transducer and activator of transcription


Vomeronasal sensory neuron



The generous support by Carlsbergfondet, Beckett-Fonden and Augustinus Fonden is gratefully acknowledged. The authors would like to thank Janne Nielsen for helpful comments on the manuscript.


  1. 1.
    Basch ML, Garcia-Castro MI, Bronner-Fraser M (2004) Molecular mechanisms of neural crest induction. Birth Defects Res C Embryo Today 72:109-123PubMedCrossRefGoogle Scholar
  2. 2.
    Tessier-Lavigne M, Goodman CS (1996) The molecular biology of axon guidance. Science 274:1123-1133PubMedCrossRefGoogle Scholar
  3. 3.
    Walmod PS, Pedersen MV, Berezin V, Bock E (2007) Cell adhesion molecules of the immunoglobulin superfamily in the nervous system. In: Lajtha A, Banik N (eds) Handbook of neurochemistry and molecular neurobiology, vol 7, Neural protein metabolism and function. Springer, New York, pp 35-152CrossRefGoogle Scholar
  4. 4.
    Bartsch U (2003) Neural CAMS and their role in the development and organization of myelin sheaths. Front Biosci 8:d477-d490PubMedCrossRefGoogle Scholar
  5. 5.
    Cotman CW, Hailer NP, Pfister KK, Soltesz I, Schachner M (1998) Cell adhesion molecules in neural plasticity and pathology: similar mechanisms, distinct organizations? Prog Neurobiol 55:659-669PubMedCrossRefGoogle Scholar
  6. 6.
    Massaro AR (2002) The role of NCAM in remyelination. Neurol Sci 22:429-435PubMedCrossRefGoogle Scholar
  7. 7.
    Welzl H, Stork O (2003) Cell adhesion molecules: key players in memory consolidation? News Physiol Sci 18:147-150PubMedGoogle Scholar
  8. 8.
    Rutishauser U, Thiery JP, Brackenbury R, Sela BA, Edelman GM (1976) Mechanisms of adhesion among cells from neural tissues of the chick embryo. Proc Natl Acad Sci USA 73:577-581PubMedCrossRefGoogle Scholar
  9. 9.
    Jorgensen OS, Bock E (1974) Brain specific synaptosomal membrane proteins demonstrated by crossed immunoelectrophoresis. J Neurochem 23:879-880PubMedCrossRefGoogle Scholar
  10. 10.
    Alenius M, Bohm S (1997) Identification of a novel neural cell adhesion molecule-related gene with a potential role in selective axonal projection. J Biol Chem 272:26083-26086PubMedCrossRefGoogle Scholar
  11. 11.
    Yoshihara Y, Mori K (1997) Basic principles and molecular mechanisms of olfactory axon pathfinding. Cell Tissue Res 290:457-463PubMedCrossRefGoogle Scholar
  12. 12.
    Fujita SC, Mori K, Imamura K, Obata K (1985) Subclasses of olfactory receptor cells and their segregated central projections demonstrated by a monoclonal antibody. Brain Res 326:192-196PubMedCrossRefGoogle Scholar
  13. 13.
    Yoshihara Y, Katoh K, Mori K (1993) Odor stimulation causes disappearance of R4B12 epitope on axonal surface molecule of olfactory sensory neurons. Neuroscience 53:101-110PubMedCrossRefGoogle Scholar
  14. 14.
    Schwob JE, Gottlieb DI (1986) The primary olfactory projection has two chemically distinct zones. J Neurosci 6:3393-3404PubMedGoogle Scholar
  15. 15.
    Schwob JE, Gottlieb DI (1988) Purification and characterization of an antigen that is spatially segregated in the primary olfactory projection. J Neurosci 8:3470-3480PubMedGoogle Scholar
  16. 16.
    Paoloni-Giacobino A, Chen H, Antonarakis SE (1997) Cloning of a novel human neural cell adhesion molecule gene (NCAM2) that maps to chromosome region 21q21 and is potentially involved in Down syndrome. Genomics 43:43-51PubMedCrossRefGoogle Scholar
  17. 17.
    Yoshihara Y, Kawasaki M, Tamada A, Fujita H, Hayashi H, Kagamiyama H, Mori K (1997) OCAM: a new member of the neural cell adhesion molecule family related to zone-to-zone projection of olfactory and vomeronasal axons. J Neurosci 17:5830-5842PubMedGoogle Scholar
  18. 18.
    Rogers S, Wells R, Rechsteiner M (1986) Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis. Science 234:364-368PubMedCrossRefGoogle Scholar
  19. 19.
    Kolkova K, Pedersen N, Berezin V, Bock E (2000) Identification of an amino acid sequence motif in the cytoplasmic domain of the NCAM-140 kDa isoform essential for its neuritogenic activity. J Neurochem 75:1274-1282PubMedCrossRefGoogle Scholar
  20. 20.
    Albach C, Damoc E, Denzinger T, Schachner M, Przybylski M, Schmitz B (2004) Identification of N-glycosylation sites of the murine neural cell adhesion molecule NCAM by MALDI-TOF and MALDI-FTICR mass spectrometry. Anal Bioanal Chem 378:1129-1135PubMedCrossRefGoogle Scholar
  21. 21.
    Liedtke S, Geyer H, Wuhrer M, Geyer R, Frank G, Gerardy-Schahn R, Zahringer U, Schachner M (2001) Characterization of N-glycans from mouse brain neural cell adhesion molecule. Glycobiology 11:373-384PubMedCrossRefGoogle Scholar
  22. 22.
    Wuhrer M, Geyer H, von der Ohe M, Gerardy-Schahn R, Schachner M, Geyer R (2003) Localization of defined carbohydrate epitopes in bovine polysialylated NCAM. Biochimie 85:207-218PubMedCrossRefGoogle Scholar
  23. 23.
    Edelman GM, Chuong CM (1982) Embryonic to adult conversion of neural cell adhesion molecules in normal and staggerer mice. Proc Natl Acad Sci USA 79:7036-7040PubMedCrossRefGoogle Scholar
  24. 24.
    Bonfanti L (2006) PSA-NCAM in mammalian structural plasticity and neurogenesis. Prog Neurobiol 80:129-164PubMedCrossRefGoogle Scholar
  25. 25.
    Kruse J, Mailhammer R, Wernecke H, Faissner A, Sommer I, Goridis C, Schachner M (1984) Neural cell adhesion molecules and myelin-associated glycoprotein share a common carbohydrate moiety recognized by monoclonal antibodies L2 and HNK-1. Nature 311:153-155PubMedCrossRefGoogle Scholar
  26. 26.
    Cole GJ, Schachner M (1987) Localization of the L2 monoclonal antibody binding site on chicken neural cell adhesion molecule (NCAM) and evidence for its role in NCAM-mediated cell adhesion. Neurosci Lett 78:227-232PubMedCrossRefGoogle Scholar
  27. 27.
    Holm J, Hillenbrand R, Steuber V, Bartsch U, Moos M, Lubbert H, Montag D, Schachner M (1996) Structural features of a close homologue of L1 (CHL1) in the mouse: a new member of the L1 family of neural recognition molecules. Eur J NeuroSci 8:1613-1629PubMedCrossRefGoogle Scholar
  28. 28.
    Hillenbrand R, Molthagen M, Montag D, Schachner M (1999) The close homologue of the neural adhesion molecule L1 (CHL1): patterns of expression and promotion of neurite outgrowth by heterophilic interactions. Eur J NeuroSci 11:813-826PubMedCrossRefGoogle Scholar
  29. 29.
    McGarry RC, Helfand SL, Quarles RH, Roder JC (1983) Recognition of myelin-associated glycoprotein by the monoclonal antibody HNK-1. Nature 306:376-378PubMedCrossRefGoogle Scholar
  30. 30.
    Shih IM, Elder DE, Hsu MY, Herlyn M (1994) Regulation of Mel-CAM/MUC18 expression on melanocytes of different stages of tumor progression by normal keratinocytes. Am J Pathol 145:837-845PubMedGoogle Scholar
  31. 31.
    Ong E, Suzuki M, Belot F, Yeh JC, Franceschini I, Angata K, Hindsgaul O, Fukuda M (2002) Biosynthesis of HNK-1 glycans on O-linked oligosaccharides attached to the neural cell adhesion molecule (NCAM): the requirement for core 2 beta 1, 6-N-acetylglucosaminyltransferase and the muscle-specific domain in NCAM. J Biol Chem 277:18182-18190PubMedCrossRefGoogle Scholar
  32. 32.
    Kleene R, Schachner M (2004) Glycans and neural cell interactions. Nat Rev Neurosci 5:195-208PubMedCrossRefGoogle Scholar
  33. 33.
    Yu RK, Yanagisawa M (2006) Glycobiology of neural stem cells. CNS Neurol Disord Drug Targets 5:415-423PubMedCrossRefGoogle Scholar
  34. 34.
    Little EB, Edelman GM, Cunningham BA (1998) Palmitoylation of the cytoplasmic domain of the neural cell adhesion molecule N-CAM serves as an anchor to cellular membranes. Cell Adhes Commun 6:415-430PubMedCrossRefGoogle Scholar
  35. 35.
    Niethammer P, Delling M, Sytnyk V, Dityatev A, Fukami K, Schachner M (2002) Cosignaling of NCAM via lipid rafts and the FGF receptor is required for neuritogenesis. J Cell Biol 157:521-532PubMedCrossRefGoogle Scholar
  36. 36.
    Little EB, Crossin KL, Krushel LA, Edelman GM, Cunningham BA (2001) A short segment within the cytoplasmic domain of the neural cell adhesion molecule (N-CAM) is essential for N-CAM-induced NF-kappa B activity in astrocytes. Proc Natl Acad Sci USA 98:2238-2243PubMedCrossRefGoogle Scholar
  37. 37.
    Kaltschmidt B, Widera D, Kaltschmidt C (2005) Signaling via NF-kappaB in the nervous system. Biochim Biophys Acta 1745:287-299PubMedCrossRefGoogle Scholar
  38. 38.
    Polo-Parada L, Plattner F, Bose C, Landmesser LT (2005) NCAM 180 acting via a conserved C-terminal domain and MLCK is essential for effective transmission with repetitive stimulation. Neuron 46:917-931PubMedCrossRefGoogle Scholar
  39. 39.
    von Campenhausen H, Yoshihara Y, Mori K (1997) OCAM reveals segregated mitral/tufted cell pathways in developing accessory olfactory bulb. NeuroReport 8:2607-2612CrossRefGoogle Scholar
  40. 40.
    Treloar HB, Gabeau D, Yoshihara Y, Mori K, Greer CA (2003) Inverse expression of olfactory cell adhesion molecule in a subset of olfactory axons and a subset of mitral/tufted cells in the developing rat main olfactory bulb. J Comp Neurol 458:389-403PubMedCrossRefGoogle Scholar
  41. 41.
    Kiselyov VV, Soroka V, Berezin V, Bock E (2005) Structural biology of NCAM homophilic binding and activation of FGFR. J Neurochem 94:1169-1179PubMedCrossRefGoogle Scholar
  42. 42.
    Kasper C, Rasmussen H, Kastrup JS, Ikemizu S, Jones EY, Berezin V, Bock E, Larsen IK (2000) Structural basis of cell-cell adhesion by NCAM. Nat Struct Biol 7:389-393PubMedCrossRefGoogle Scholar
  43. 43.
    Soroka V, Kolkova K, Kastrup JS, Diederichs K, Breed J, Kiselyov VV, Poulsen FM, Larsen IK, Welte W, Berezin V, Bock E, Kasper C (2003) Structure and interactions of NCAM Ig1-2-3 suggest a novel zipper mechanism for homophilic adhesion. Structure 11:1291-1301PubMedCrossRefGoogle Scholar
  44. 44.
    Walmod PS, Kolkova K, Berezin V, Bock E (2004) Zippers make signals: NCAM-mediated molecular interactions and signal transduction. Neurochem Res 29:2015-2035PubMedCrossRefGoogle Scholar
  45. 45.
    Cole GJ, Loewy A, Cross NV, Akeson R, Glaser L (1986) Topographic localization of the heparin-binding domain of the neural cell adhesion molecule N-CAM. J Cell Biol 103:1739-1744PubMedCrossRefGoogle Scholar
  46. 46.
    Kulahin N, Rudenko O, Kiselyov V, Poulsen FM, Berezin V, Bock E (2005) Modulation of the homophilic interaction between the first and second Ig modules of neural cell adhesion molecule by heparin. J Neurochem 95:46-55PubMedCrossRefGoogle Scholar
  47. 47.
    Kiselyov VV, Skladchikova G, Hinsby AM, Jensen PH, Kulahin N, Soroka V, Pedersen N, Tsetlin V, Poulsen FM, Berezin V, Bock E (2003) Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure 11:691-701PubMedCrossRefGoogle Scholar
  48. 48.
    Dzhandzhugazyan K, Bock E (1993) Demonstration of (Ca(2+)-Mg2+)-ATPase activity of the neural cell adhesion molecule. FEBS Lett 336:279-283PubMedCrossRefGoogle Scholar
  49. 49.
    Hubschmann MV, Skladchikova G, Bock E, Berezin V (2005) Neural cell adhesion molecule function is regulated by metalloproteinase-mediated ectodomain release. J Neurosci Res 80:826-837PubMedCrossRefGoogle Scholar
  50. 50.
    Bodrikov V, Leshchyns’ka I, Sytnyk V, Overvoorde J, den Hertog J, Schachner M (2005) RPTPalpha is essential for NCAM-mediated p59fyn activation and neurite elongation. J Cell Biol 168:127-139PubMedCrossRefGoogle Scholar
  51. 51.
    Buttner B, Kannicht C, Reutter W, Horstkorte R (2003) The neural cell adhesion molecule is associated with major components of the cytoskeleton. Biochem Biophys Res Commun 310:967-971PubMedCrossRefGoogle Scholar
  52. 52.
    Buttner B, Kannicht C, Reutter W, Horstkorte R (2005) Novel cytosolic binding partners of the neural cell adhesion molecule: mapping the binding domains of PLC gamma, LANP, TOAD-64, syndapin, PP1, and PP2A. Biochemistry 44:6938-6947PubMedCrossRefGoogle Scholar
  53. 53.
    Skaper SD, Moore SE, Walsh FS (2001) Cell signalling cascades regulating neuronal growth-promoting and inhibitory cues. Prog Neurobiol 65:593-608PubMedCrossRefGoogle Scholar
  54. 54.
    Alenius M, Bohm S (2003) Differential function of RNCAM isoforms in precise target selection of olfactory sensory neurons. Development 130:917-927PubMedCrossRefGoogle Scholar
  55. 55.
    Hamlin JA, Fang H, Schwob JE (2004) Differential expression of the mammalian homologue of fasciclin II during olfactory development in vivo and in vitro. J Comp Neurol 474:438-452PubMedCrossRefGoogle Scholar
  56. 56.
    Nagao H, Yoshihara Y, Mitsui S, Fujisawa H, Mori K (2000) Two mirror-image sensory maps with domain organization in the mouse main olfactory bulb. NeuroReport 11:3023-3027PubMedCrossRefGoogle Scholar
  57. 57.
    Ressler KJ, Sullivan SL, Buck LB (1993) A zonal organization of odorant receptor gene expression in the olfactory epithelium. Cell 73:597-609PubMedCrossRefGoogle Scholar
  58. 58.
    Ressler KJ, Sullivan SL, Buck LB (1994) Information coding in the olfactory system: evidence for a stereotyped and highly organized epitope map in the olfactory bulb. Cell 79:1245-1255PubMedCrossRefGoogle Scholar
  59. 59.
    Vassar R, Ngai J, Axel R (1993) Spatial segregation of odorant receptor expression in the mammalian olfactory epithelium. Cell 74:309-318PubMedCrossRefGoogle Scholar
  60. 60.
    Chehrehasa F, St John J, Key B (2005) The sorting behaviour of olfactory and vomeronasal axons during regeneration. J Mol Histol 36:427-436PubMedCrossRefGoogle Scholar
  61. 61.
    Walz A, Mombaerts P, Greer CA, Treloar HB (2006) Disrupted compartmental organization of axons and dendrites within olfactory glomeruli of mice deficient in the olfactory cell adhesion molecule, OCAM. Mol Cell Neurosci 32:1-14PubMedCrossRefGoogle Scholar
  62. 62.
    Gussing F, Bohm S (2004) NQO1 activity in the main and the accessory olfactory systems correlates with the zonal topography of projection maps. Eur J NeuroSci 19:2511-2518PubMedCrossRefGoogle Scholar
  63. 63.
    Norlin EM, Berghard A (2001) Spatially restricted expression of regulators of G-protein signaling in primary olfactory neurons. Mol Cell Neurosci 17:872-882PubMedCrossRefGoogle Scholar
  64. 64.
    Oka Y, Kobayakawa K, Nishizumi H, Miyamichi K, Hirose S, Tsuboi A, Sakano H (2003) O-MACS, a novel member of the medium-chain acyl-CoA synthetase family, specifically expressed in the olfactory epithelium in a zone-specific manner. Eur J Biochem 270:1995-2004PubMedCrossRefGoogle Scholar
  65. 65.
    Cooper BG, Mizumori SJ (2001) Temporary inactivation of the retrosplenial cortex causes a transient reorganization of spatial coding in the hippocampus. J Neurosci 21:3986-4001PubMedGoogle Scholar
  66. 66.
    Ichinohe N, Knight A, Ogawa M, Ohshima T, Mikoshiba K, Yoshihara Y, Terashima T, Rockland KS (2007) Unusual patch matrix organization in the retrosplenial cortex of the reeler mouse and shaking rat kawasaki. Cereb Cortex 18:1125-1138PubMedCrossRefGoogle Scholar
  67. 67.
    Ichinohe N, Yoshihara Y, Hashikawa T, Rockland KS (2003) Developmental study of dendritic bundles in layer 1 of the rat granular retrosplenial cortex with special reference to a cell adhesion molecule, OCAM. Eur J NeuroSci 18:1764-1774PubMedCrossRefGoogle Scholar
  68. 68.
    Sutherland RJ, Whishaw IQ, Kolb B (1988) Contributions of cingulate cortex to two forms of spatial learning and memory. J Neurosci 8:1863-1872PubMedGoogle Scholar
  69. 69.
    Molloy CA, Keddache M, Martin LJ (2005) Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression. Mol Psychiatry 10:741-746PubMedCrossRefGoogle Scholar
  70. 70.
    Akeson EC, Lambert JP, Narayanswami S, Gardiner K, Bechtel LJ, Davisson MT (2001) Ts65Dn - localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome. Cytogenet Cell Genet 93:270-276PubMedCrossRefGoogle Scholar
  71. 71.
    Xu LL, Su YP, Labiche R, Segawa T, Shanmugam N, McLeod DG, Moul JW, Srivastava S (2001) Quantitative expression profile of androgen-regulated genes in prostate cancer cells and identification of prostate-specific genes. Int J Cancer 92:322-328PubMedCrossRefGoogle Scholar
  72. 72.
    Edwards S, Campbell C, Flohr P, Shipley J, Giddings I, Te-Poele R, Dodson A, Foster C, Clark J, Jhavar S, Kovacs G, Cooper CS (2005) Expression analysis onto microarrays of randomly selected cDNA clones highlights HOXB13 as a marker of human prostate cancer. Br J Cancer 92:376-381PubMedCrossRefGoogle Scholar
  73. 73.
    Nelson EA, Walker SR, Li W, Liu XS, Frank DA (2006) Identification of human STAT5-dependent gene regulatory elements based on interspecies homology. J Biol Chem 281:26216-26224PubMedCrossRefGoogle Scholar
  74. 74.
    Jensen PH, Soroka V, Thomsen NK, Ralets I, Berezin V, Bock E, Poulsen FM (1999) Structure and interactions of NCAM modules 1 and 2, basic elements in neural cell adhesion. Nat Struct Biol 6:486-493PubMedCrossRefGoogle Scholar
  75. 75.
    Blom N, Sicheritz-Ponten T, Gupta R, Gammeltoft S, Brunak S (2004) Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics 4:1633-1649PubMedCrossRefGoogle Scholar
  76. 76.
    Zhou F, Xue Y, Yao X, Xu Y (2006) CSS-Palm: palmitoylation site prediction with a clustering and scoring strategy (CSS). Bioinformatics 22:894-896PubMedCrossRefGoogle Scholar
  77. 77.
    Puntervoll P, Linding R, Gemund C, Chabanis-Davidson S, Mattingsdal M, Cameron S, Martin DM, Ausiello G, Brannetti B, Costantini A, Ferre F, Maselli V, Via A, Cesareni G, Diella F, Superti-Furga G, Wyrwicz L, Ramu C, McGuigan C, Gudavalli R, Letunic I, Bork P, Rychlewski L, Kuster B, Helmer-Citterich M, Hunter WN, Aasland R, Gibson TJ (2003) ELM server: a new resource for investigating short functional sites in modular eukaryotic proteins. Nucleic Acids Res 31:3625-3630PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Protein Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health SciencesUniversity of Copenhagen, Panum InstituteCopenhagenDenmark

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