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Gene Review

Cntnap1  -  contactin associated protein 1

Rattus norvegicus

Synonyms: Caspr, Caspr1, Contactin-associated protein 1, Neurexin IV, Neurexin-4, ...
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Disease relevance of Cntnap1

  • GAP and two associated proteins, p62 and p190, were shown to be phosphorylated on tyrosine in the LSTRA thymoma cell line, in which the p56lck tyrosine kinase is overexpressed as a result of retroviral promoter insertion [1].

Psychiatry related information on Cntnap1

  • Inhibition of the p190 RhoGAP-downstream kinase ROCK in LA during fear conditioning impaired long- but not short-term memory [2].

High impact information on Cntnap1


Biological context of Cntnap1

  • The formation of these specialized axoglial contacts depends on the presence of three cell adhesion molecules: neurofascin 155 on the glial membrane and a complex of Caspr and contactin on the axon [7].
  • We have identified two closely linked tyrosine-containing peptides in p190 that bind simultaneously to the RasGAP SH2 domains upon p190 phosphorylation [8].
  • In addition, it appears that the role of p190 in the RasGAP signaling complex is to promote additional protein interactions with RasGAP via its SH3 domain [8].
  • A survey of rat tissues by immunoblotting indicated that p190 is expressed predominantly in the adult forebrain and cerebellum, and could be detected in embryos 11 d post coitus [9].
  • While the purified protein is unable to hydrolyze GTP, we detect an activity in cell lysates that can promote GTP hydrolysis by p190 [10].

Anatomical context of Cntnap1

  • Caspr is poorly extracted by nonionic detergents, suggesting that it is associated with the axon cytoskeleton at these junctions [11].
  • In contrast, Caspr expression initially remains elevated along segments of neurites associated with nascent myelin sheaths [11].
  • Caspr expression is similarly restricted to the paranodes of mature myelinated axons in the peripheral and central nervous systems; it is more diffusely and persistently expressed in gray matter and on unmyelinated axons [11].
  • In Shiverer mutant mice, which assemble neither compact CNS myelin nor normal paranodes, NF155 (though largely retained at the cell body) is also distributed at ectopic sites along axons, where it colocalizes with Caspr1 [12].
  • Concentration of NF155 with Caspr1 at the paranodal junctions of peripheral nerves is also a feature of Schwann cells [12].

Associations of Cntnap1 with chemical compounds

  • In contrast, the majority of GAP enters a distinct complex with p190 that is exclusively cytosolic and contains predominantly phosphoserine [13].
  • The sequence of p190 in the GTP-binding domain, which shares structural features with both the Ras-like small GTPases and the larger G proteins, suggests that this protein defines a novel class of guanine nucleotide-binding proteins [10].
  • In SH-SY5Y cells, only the combination of insulin and C-peptide normalized posttranslational O-linked N-acetylglucosamine modifications and maximized serine phosphorylation of ankyrin(G) and p85 binding to caspr [14].
  • The FSH-enhanced phosphotyrosine (p-Tyr) level of p190 RhoGAP was selectively reduced by the overexpressed wild type, but not by mutated PTP20 [15].
  • The CS and DA mutants as well as the wild type reduced the formation of p190 RhoGAP-p120 RasGAP complexes [15].

Co-localisations of Cntnap1

  • We now report that contactin colocalizes and forms a cis complex with Caspr in the paranodes and juxtamesaxon [16].

Other interactions of Cntnap1

  • These results indicate that contactin and Caspr function independently during myelination and that their expression is regulated by glial ensheathment [11].
  • The known molecular components of paranodes--contactin, Caspr, and neurofascin 155--are not clustered in md spinal cords, and no septate-like junctions between oligodendrocyte processes and axons are found by electron microscopy [17].
  • We observed that dysmyelination is associated with dispersed labeling of Kv1.1 and Kv1.2 K+ channel subunits, as well as Caspr, a protein normally confined to paranodes, along the LES rat spinal cord axons [18].

Analytical, diagnostic and therapeutic context of Cntnap1

  • Immunoelectron microscopy demonstrated that Caspr is localized to the septate-like junctions that form between axons and the paranodal loops of myelinating cells [11].
  • Confocal microscopy analysis revealed that PTP20 intracellularly colocalizes with p190 RhoGAP [15].
  • One sequence of particular interest, 25.2, is up-regulated after castration and is homologous to p190, a protein associated with cytoskeletal reorganization [19].
  • Sections from experimental and normal control IONs were double-stained for indirect immunofluorescence using an antibody that identifies all NaCh isoforms and caspr-antibody to identify nodes of Ranvier, and a confocal microscope z-series of optically sectioned images were then obtained [20].


  1. Tyrosine phosphorylation of GAP and GAP-associated proteins in lymphoid and fibroblast cells expressing lck. Ellis, C., Liu, X.Q., Anderson, D., Abraham, N., Veillette, A., Pawson, T. Oncogene (1991) [Pubmed]
  2. Fear memory formation involves p190 RhoGAP and ROCK proteins through a GRB2-mediated complex. Lamprecht, R., Farb, C.R., LeDoux, J.E. Neuron (2002) [Pubmed]
  3. Regulating axon branch stability: the role of p190 RhoGAP in repressing a retraction signaling pathway. Billuart, P., Winter, C.G., Maresh, A., Zhao, X., Luo, L. Cell (2001) [Pubmed]
  4. Molecular cloning of cDNAs encoding the GAP-associated protein p190: implications for a signaling pathway from ras to the nucleus. Settleman, J., Narasimhan, V., Foster, L.C., Weinberg, R.A. Cell (1992) [Pubmed]
  5. Phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases. Ellis, C., Moran, M., McCormick, F., Pawson, T. Nature (1990) [Pubmed]
  6. Paranodin, a glycoprotein of neuronal paranodal membranes. Menegoz, M., Gaspar, P., Le Bert, M., Galvez, T., Burgaya, F., Palfrey, C., Ezan, P., Arnos, F., Girault, J.A. Neuron (1997) [Pubmed]
  7. Spectrins and ankyrinB constitute a specialized paranodal cytoskeleton. Ogawa, Y., Schafer, D.P., Horresh, I., Bar, V., Hales, K., Yang, Y., Susuki, K., Peles, E., Stankewich, M.C., Rasband, M.N. J. Neurosci. (2006) [Pubmed]
  8. Tandem SH2 binding sites mediate the RasGAP-RhoGAP interaction: a conformational mechanism for SH3 domain regulation. Hu, K.Q., Settleman, J. EMBO J. (1997) [Pubmed]
  9. Biochemical and immunological characterization of p190-calmodulin complex from vertebrate brain: a novel calmodulin-binding myosin. Espindola, F.S., Espreafico, E.M., Coelho, M.V., Martins, A.R., Costa, F.R., Mooseker, M.S., Larson, R.E. J. Cell Biol. (1992) [Pubmed]
  10. p190 RhoGAP, the major RasGAP-associated protein, binds GTP directly. Foster, R., Hu, K.Q., Shaywitz, D.A., Settleman, J. Mol. Cell. Biol. (1994) [Pubmed]
  11. The axonal membrane protein Caspr, a homologue of neurexin IV, is a component of the septate-like paranodal junctions that assemble during myelination. Einheber, S., Zanazzi, G., Ching, W., Scherer, S., Milner, T.A., Peles, E., Salzer, J.L. J. Cell Biol. (1997) [Pubmed]
  12. An oligodendrocyte cell adhesion molecule at the site of assembly of the paranodal axo-glial junction. Tait, S., Gunn-Moore, F., Collinson, J.M., Huang, J., Lubetzki, C., Pedraza, L., Sherman, D.L., Colman, D.R., Brophy, P.J. J. Cell Biol. (2000) [Pubmed]
  13. Protein-tyrosine kinases regulate the phosphorylation, protein interactions, subcellular distribution, and activity of p21ras GTPase-activating protein. Moran, M.F., Polakis, P., McCormick, F., Pawson, T., Ellis, C. Mol. Cell. Biol. (1991) [Pubmed]
  14. Molecular alterations underlie nodal and paranodal degeneration in type 1 diabetic neuropathy and are prevented by C-peptide. Sima, A.A., Zhang, W., Li, Z.G., Murakawa, Y., Pierson, C.R. Diabetes (2004) [Pubmed]
  15. Protein tyrosine phosphatase PTP20 induces actin cytoskeleton reorganization by dephosphorylating p190 RhoGAP in rat ovarian granulosa cells stimulated with follicle-stimulating hormone. Shiota, M., Tanihiro, T., Nakagawa, Y., Aoki, N., Ishida, N., Miyazaki, K., Ullrich, A., Miyazaki, H. Mol. Endocrinol. (2003) [Pubmed]
  16. Contactin-associated protein (Caspr) and contactin form a complex that is targeted to the paranodal junctions during myelination. Rios, J.C., Melendez-Vasquez, C.V., Einheber, S., Lustig, M., Grumet, M., Hemperly, J., Peles, E., Salzer, J.L. J. Neurosci. (2000) [Pubmed]
  17. Genetic dysmyelination alters the molecular architecture of the nodal region. Arroyo, E.J., Xu, T., Grinspan, J., Lambert, S., Levinson, S.R., Brophy, P.J., Peles, E., Scherer, S.S. J. Neurosci. (2002) [Pubmed]
  18. Structural and functional alterations of spinal cord axons in adult Long Evans Shaker (LES) dysmyelinated rats. Eftekharpour, E., Karimi-Abdolrezaee, S., Sinha, K., Velumian, A.A., Kwiecien, J.M., Fehlings, M.G. Exp. Neurol. (2005) [Pubmed]
  19. Expression of p190A during apoptosis in the regressing rat ventral prostate. Morrissey, C., Bennett, S., Nitsche, E., Guenette, R.S., Wong, P., Tenniswood, M. Endocrinology (1999) [Pubmed]
  20. Increased sodium channel immunofluorescence at myelinated and demyelinated sites following an inflammatory and partial axotomy lesion of the rat infraorbital nerve. Henry, M.A., Freking, A.R., Johnson, L.R., Levinson, S.R. Pain (2006) [Pubmed]
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