Intracelluar Ligands of NCAM

  • Bettina Büttner
  • Rüdiger HorstkorteEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 663)


The neural cell adhesion molecule (NCAM) was identified as one of the first members of the immunoglobulin superfamily. It is implicated in numerous cellular functions. Thus, during embryonic development it controls tissue formation (e.g., neurulation) and is involved in many processes of neuronal development such as migration of neuroblasts, regulated outgrowth and fasciculation of neurites, and the formation of communication contacts, for example nerve-muscle cell interactions. Furthermore, NCAM is involved in synaptogenesis and synaptic plasticity, learning and memory processes as well as regeneration. NCAM is a Ca2+-independent homophilic cell adhesion molecule, existing in three major isoforms, which are generated by alternative splicing of a single gene. Taking into account, their apparent molecular weights, they are termed NCAM 120, NCAM 140 and NCAM 180. NCAM 120 is anchored to the membrane via glycosyl-phosphatidyl-inositol, whereas NCAM 140 and NCAM 180 are transmembrane glycoproteins with large intracellular domains of different length. The purpose of this overview is to summarize the current knowledge on the intracellular binding partners of NCAM 140 and NCAM 180.


Cytoskeleton Signal transduction Neural cell adhesion molecule Protein-protein interaction Neurite outgrowth Regeneration 


  1. 1.
    Edelman GM, Crossin KL (1991) Cell adhesion molecules. Implications for a molecular histology. Annu Rev Biochem 60:155-190PubMedCrossRefGoogle Scholar
  2. 2.
    Hinsby AM, Berezin V, Bock E (2004) Molecular mechanisms of NCAM function. Front Biosci 9:2227-2244PubMedCrossRefGoogle Scholar
  3. 3.
    Maness PF, Schachner M (2007) Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat Neurosci 101:19-26CrossRefGoogle Scholar
  4. 4.
    Jorgensen OS, Bock E (1974) Brain specific synaptosomal membrane proteins demonstrated by crossed immunoelectrophoresis. J Neurochem. 23(879):880Google Scholar
  5. 5.
    Thiery J-P, Brackenbury R, Rutishauser U, Edelman GM (1977) Adhesion among neural cells of the chick embryo. II. Purification and characterization of a cell adhesion molecule from neural retina. J Biol Chem 252:6841-6845PubMedGoogle Scholar
  6. 6.
    Barbas JA, Chaix JC, Steinmetz M, Goridis C (1988) Differential splicing and alternative polyadenylation generates distinct N-CAM transcripts and proteins in the mouse. EMBO J 7:625-632PubMedGoogle Scholar
  7. 7.
    Covault J, Merlie JP, Goridis C, Sanes JR (1986) Molecular forms of N-CAM and its RNA in developing and denervated skeletal muscle. J Cell Biol 102:716-730PubMedCrossRefGoogle Scholar
  8. 8.
    Murray BA, Owens GC, Prediger EA, Crossin KL, Cunningham BA, Edelman GM (1986) Cell surface modulation of the neural cell adhesion molecule resulting from alternative mRNA splicing in a tissue-specific developmental sequence. J Cell Biol 103:1431-1439PubMedCrossRefGoogle Scholar
  9. 9.
    Pollerberg EG, Burridge K, Krebs S, Goodman S, Schachner M (1987) The 180 kD component of the neural cell adhesion molecule N-CAM is involved in cell-cell contacts and cytoskeleton-membrane interactions. Cell Tiss Res 250:227-236CrossRefGoogle Scholar
  10. 10.
    Persohn E, Schachner M (1987) Immunoelectron microscopic localization of the neural cell adhesion molecules L1 and N-CAM during postnatal development of the mouse cerebellum. J Cell Biol 105:569-576PubMedCrossRefGoogle Scholar
  11. 11.
    Pollerberg EG, Sadoul R, Goridis C, Schachner M (1985) Selective expression of the 180-kD component of the neural cell adhesion molecule N-CAM during development. J Cell Biol 101:1921-1929PubMedCrossRefGoogle Scholar
  12. 12.
    Pollerberg EG, Schachner M, Davoust J (1986) Differentiation state-dependent surface mobilities of two forms of the neural cell adhesion molecule. Nature 324:462-465PubMedCrossRefGoogle Scholar
  13. 13.
    Leshchyns’ka I, Sytnyk V, Morrow JS, Schachner M (2003) Neural cell adhesion molecule (NCAM) association with PKCbeta2 via betaI spectrin is implicated in NCAM-mediated neurite outgrowth. J Cell Biol 161:625-639PubMedCrossRefGoogle Scholar
  14. 14.
    Büttner B (2004) The role of the cytoplasmic domains of the neural cell adhesion molecule in neurite outgrowth and identification of novel intracellular binding partners. PhD Thesis, FU Berlin.
  15. 15.
    Bloch RJ, Morrow JS (1989) An unusual beta-spectrin associated with clustered acetylcholine receptors. J Cell Biol 108:481-493PubMedCrossRefGoogle Scholar
  16. 16.
    Rodriguez MM, Ron D, Touhara K, Chen CH, Mochly-Rosen D (1999) RACK1, a protein kinase C anchoring protein, coordinates the binding of activated protein kinase C and select pleckstrin homology domains in vitro. Biochemistry 3842:13787-13794CrossRefGoogle Scholar
  17. 17.
    Kolkova K, Novitskaya V, Pedersen N, Berezin V, Bock E (2000) Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway. J Neurosci 20:2238-2246PubMedGoogle Scholar
  18. 18.
    Sytnyk V, Leshchyns’ka I, Nikonenko AG, Schachner M (2006) NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex. J Cell Biol 174:1071-1085PubMedCrossRefGoogle Scholar
  19. 19.
    Wechsler A, Teichberg VI (1998) Brain spectrin binding to the NMDA receptor is regulated by phosphorylation, calcium and calmodulin. EMBO J 17:3931-3939PubMedCrossRefGoogle Scholar
  20. 20.
    Müller D, Wang C, Skibo G, Toni N, Cremer H, Calaora V, Rougon G, Kiss JZ (1996) PSA-NCAM is required for activity-induced synaptic plasticity. Neuron 17:413-422PubMedCrossRefGoogle Scholar
  21. 21.
    Bukalo O, Fentrop N, Lee AY, Salmen B, Law JW, Wotjak CT, Schweizer M, Dityatev A, Schachner M (2004) Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus. J Neurosci. 24:1565-1577PubMedCrossRefGoogle Scholar
  22. 22.
    Beggs HE, Baragona SC, Hemperly JJ, Maness PF (1997) NCAM140 interacts with the focal adhesion kinase p125(fak) and the SRC-related tyrosine kinase p59(fyn). J Biol Chem 272:8310-8319PubMedCrossRefGoogle Scholar
  23. 23.
    Schmid RS Graff, RD SMD, Chen S, Schachner M, Hemperly JJ, Maness PF (1999) NCAM stimulates the Ras-MAPK pathway and CREB phosphorylation in neuronal cells. J Neurobiol 38:542-558PubMedCrossRefGoogle Scholar
  24. 24.
    Zheng XM, Wang Y, Pallen CJ (1992) Cell transformation and activation of pp 60c-src by overexpression of a protein tyrosine phosphatase. Nature 359:336-339PubMedCrossRefGoogle Scholar
  25. 25.
    Zheng XM, Resnick RJ, Shalloway D (2000) A phosphotyrosine displacement mechanism for activation of Src by PTPalpha. EMBO J 19:964-978PubMedCrossRefGoogle Scholar
  26. 26.
    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
  27. 27.
    Büttner B, Reutter W, Horstkorte R (2004) The cytoplasmic domain of NCAM 180 reduces NCAM-mediated neurite outgrowth. J Neurosci Res 75:854-860PubMedCrossRefGoogle Scholar
  28. 28.
    Büttner 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
  29. 29.
    Büttner B, Kannicht C, Reutter W, Horstkorte R (2005) Novel cytosolic binding partners of the neural cell adhesion molecule: mapping the binding domains of PLCγ LANP, TOAD-64, Syndapin, PP1 and PP2A. Biochemistry 44:6938-6947PubMedCrossRefGoogle Scholar
  30. 30.
    Katayose Y, Li M, Al-Murrani SW, Shenolikar S, Damuni Z (2000) Protein phosphatase 2A inhibitors, I(1)-(PP2A) and I(2)(PP2A), associate with and modify the substrate specificity of protein phosphatase 1. J Biol Chem 275:9209-9214PubMedCrossRefGoogle Scholar
  31. 31.
    Li M, Makkinje A, Damuni Z (1996) Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A. Biochemistry 35:6998-7002PubMedCrossRefGoogle Scholar
  32. 32.
    Mackie K, Sorkin BC, Nairn AC, Greengard P, Edelman GM, Cunningham BA (1989) Identification of two protein kinases that phosphorylate the neural cell-adhesion molecule N-CAM. J Neurosci 9:1883-9186PubMedGoogle Scholar
  33. 33.
    Geschwind DH, Kelly GM, Fryer H, Feeser-Bhatt H, Hockfield S (1996) Identification and characterization of novel developmentally regulated proteins in rat spinal cord. Brain Res Dev Brain Res 97:62-75PubMedCrossRefGoogle Scholar
  34. 34.
    Minturn JE, Fryer HJ, Geschwind DH, Hockfield S (1995) TOAD-64, a gene expressed early in neuronal differentiation in the rat, is related to unc-33, a C. elegans gene involved in axon outgrowth. J Neurosci 15:6757-6766PubMedGoogle Scholar
  35. 35.
    Qualmann B, Roos J, DiGregorio PJ, Kelly RB (1999) Syndapin I, a synaptic dynamin-binding protein that associates with the neural Wiskott-Aldrich syndrome protein. Mol Biol Cell 10:501-513PubMedGoogle Scholar
  36. 36.
    Qualmann B, Kelly RB (2000) Syndapin isoforms participate in receptor-mediated endocytosis and actin organization. J Cell Biol 148:1047-1062PubMedCrossRefGoogle Scholar
  37. 37.
    Minana R, Duran JM, Tomas M, Renau-Piqueras J, Guerri C (2001) Neural cell adhesion molecule is endocytosed via a clathrin-dependent pathway. Eur J NeuroSci 13:749-756PubMedCrossRefGoogle Scholar
  38. 38.
    Diestel S, Schaefer D, Cremer H, Schmitz B (2007) NCAM is ubiquitylated, endocytosed and recycled in neurons. J Cell Sci 120:4035-4049PubMedCrossRefGoogle Scholar
  39. 39.
    Kobe B, Deisenhofer J (1994) The leucine-rich repeat: a versatile binding motif. Trends Biochem Sci 19:415-421PubMedCrossRefGoogle Scholar
  40. 40.
    Kobe B, Deisenhofer J (1995) Proteins with leucine-rich repeats. Curr Opin Struct Biol 5:409-416PubMedCrossRefGoogle Scholar
  41. 41.
    Matsuoka K, Taoka M, Satozawa N, Nakayama H, Ichimura T, Takahashi N, Yamakuni T, Song SY, Isobe T (1994) A nuclear factor containing the leucine-rich repeats expressed in murine cerebellar neurons. Proc Natl Acad Sci USA 91:9670-9674PubMedCrossRefGoogle Scholar
  42. 42.
    Opal P, Garcia JJ, Propst F, Matilla A, Orr HT, Zoghbi HY (2003) Mapmodulin/leucine-rich acidic nuclear protein binds the light chain of microtubule-associated protein 1B and modulates neuritogenesis. J Biol Chem 278:34691-34699PubMedCrossRefGoogle Scholar
  43. 43.
    Ulitzur N, Rancano C, Pfeffer SR (1997) Biochemical characterization of mapmodulin, a protein that binds microtubule-associated proteins. J Biol Chem 272:30577-30582PubMedCrossRefGoogle Scholar
  44. 44.
    Ulitzur N, Humbert M, Pfeffer SR (1997) Mapmodulin: a possible modulator of the interaction of microtubule-associated proteins with microtubules. Proc Natl Acad Sci USA 94:5084-5089PubMedCrossRefGoogle Scholar
  45. 45.
    Hirayama E, Kim J (2008) Identification and characterization of a novel neural cell adhesion molecule (NCAM)-associated protein from quail myoblasts: relationship to myotube formation and induction of neurite-like protrusions. Differentiation 76(3):253-66PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Institut für Physiologische ChemieMartin-Luther-Universität Halle-WittenbergHalleGermany

Personalised recommendations