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Identification of a novel contactin‐associated transmembrane receptor with multiple domains implicated in protein–protein interactions
Open accessAbstract
Receptor protein tyrosine phosphatase beta (RPTPbeta) expressed on the surface of glial cells binds to the glycosylphosphatidylinositol (GPI)-anchored recognition molecule contactin on neuronal cells leading to neurite outgrowth. We describe the cloning of a novel contactin-associated transmembrane receptor (p190/Caspr) containing a mosaic of domains implicated in protein-protein interactions. The extracellular domain of Caspr contains a neurophilin/coagulation factor homology domain, a region related to fibrinogen beta/gamma, epidermal growth factor-like repeats, neurexin motifs as well as unique PGY repeats found in a molluscan adhesive protein. The cytoplasmic domain of Caspr contains a proline-rich sequence capable of binding to a subclass of SH3 domains of signaling molecules. Caspr and contactin exist as a complex in rat brain and are bound to each other by means of lateral (cis) interactions in the plasma membrane. We propose that Caspr may function as a signaling component of contactin, enabling recruitment and activation of intracellular signaling pathways in neurons. The binding of RPTPbeta to the contactin-Caspr complex could provide a mechanism for cell-cell communication between glial cells and neurons during development.
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“In comparison to Caspr, which becomes concentrated in the paranodal junctions of myelinated axons [49], BIN1 displayed patchy distribution along short segments of interdigitating processes without an apparent concentration in the nodes or the paranodal area (Fig. 4g).”
From Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts (2016) · cites this paper as [49]
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“In this regard, a three member gene family consisting of glial RPTPβ and the neuronal Caspr1/ contactin complex has been shown to play a role in glial-neuronal adhesiveness and cellular communications (Peles et al., 1997, 1998; Pierre et al., 1998).”
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“The contactinassociated protein (Caspr; also known as Cntnap) family, which belongs to the neurexin superfamily, is composed of five members: Caspr and Caspr2–5 (Peles et al., 1997; Bellen et al., 1998; Spiegel et al., 2002; Traut et al., 2006).”
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“Mouse Caspr5 proteins have more than a 95% similarity among each other and show a high degree of sequence and domain conservation with Caspr1 to Caspr4, which are mainly, yet not exclusively, synthesized in neurons.”
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“Interestingly, Caspr1 appears to function as the signaling component for contactin, causing activation of intracellular signaling pathways in neurons (Peles et al., 1997).”
BackgroundInfluentialMorató, X., Luján, R., Gonçalves, N., Watanabe, M., Altafaj, X., Carvalho, A. L., Fernández-Dueñas, V., Cunha, R., & Ciruela, F. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy264 · Cited by 8
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“Recently, it has been postulated that a membrane-spanning protein such as L1, RPTP or contactin-associated protein (Caspr), which has been shown to interact with both contactin and Fyn, may act as a transmembrane signal transducer (Peles et al. 1997; Zeng et al. 1999; Crossin & Krushel 2000).”
BackgroundOgawa, Y., Lim, B. C., George, S., Oses-Prieto, J., Rasband, J. M., Eshed-Eisenbach, Y., Nair, S., Boato, F., Peles, E., Burlingame, A., et al. (2023) · bioRxiv · doi:10.1101/2023.03.06.531378 · Cited by 7
Self-citationIshibashi, T., Kodama, A., & Baba, H. (2015) · Journal of Neuroscience Research · doi:10.1002/jnr.23465 · Cited by 7
“The axonal proteins contactin (Rios et al., 2000; Boyle et al., 2001) and contactin-associated protein (Caspr; Einheber et al., 1997; Peles et al., 1997) form a heteromeric complex at the paranodes.”
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4 – Potassium Channel Organization of Myelinated and Demyelinated Axons
Rasband, M. (2005) · Elsevier eBooks · doi:10.1016/b978-012738761-1/50005-5 · Cited by 7
Caspr1 Facilitates sAPPα Production by Regulating α-Secretase ADAM9 in Brain Endothelial Cells
Tang, S., Liu, D., Li, Y., Wang, K.-J., Wang, X., Su, Z.-K., Fang, W., Qin, X., Wei, J., Zhao, W., et al. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00023 · Cited by 8
Hypothalamic Glial-to-Neuronal Signaling during Puberty: Influence of Alcohol
Srivastava, V., Hiney, J., & Dees, W. (2011) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph8072894 · Cited by 6
“Since adhesion/signaling molecules are abundant in the MBH, and have cell signaling actions [23,63], it has been suggested that they play a role in intracellular communication between glial cells and LHRH neuron terminals [64,65].”
BackgroundFaissner, A. (1997) · The Neuroscientist · doi:10.1177/107385849700300610 · Cited by 5
Karbian, N., Eshed-Eisenbach, Y., Zeibak, M., Tabib, A., Sukhanov, N., Vainshtein, A., Morgan, B., Fellig, Y., Peles, E., & Mevorach, D. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02920-9 · Cited by 5
Self-citationKondiles, B. R., Murphy, R. L., Widman, A. J., Perlmutter, S. I., & Horner, P. J. (2023) · Glia · doi:10.1002/glia.24376 · Cited by 10
Uthamacumaran, A. (2022) · Biological Cybernetics · doi:10.1007/s00422-022-00935-8 · Cited by 5
Finding New Ways How to Control BACE1
Nahálková, J. (2022) · The Journal of Membrane Biology · doi:10.1007/s00232-022-00225-1 · Cited by 6
“CASPR associates with CNTN1 by cis interaction on the cytoplasmic membrane (Peles et al. 1997) and its deficiency causes the displacement of K + channels from juxtaparanodal to paranodal position, the absence of contactin in paranodes, severe decrease of the peripheral nerve conduction velocity (Bhat et al.”
BackgroundVenken, K., Meuleman, J., Irobi, J., Ceuterick, C., Martini, R., de Jonghe, P., & Timmerman, V. (2001) · NeuroReport · doi:10.1097/00001756-200108080-00063 · Cited by 5
The Neurexin and NCP Gene Families
Bhat, M. (2004) · Elsevier eBooks · doi:10.1016/b978-012439510-7/50076-0 · Cited by 5
Contactin-1 is a critical neuronal cell surface receptor for perineuronal net structure
Sinha, A., Nickerson, G., Bouyain, S., & Matthews, R. T. (2024) · bioRxiv · doi:10.1101/2024.11.05.622114 · Cited by 4
“Previous work had identified interactions between RPTP z and the GPI-linked protein Cntn1 (35) and provided a structural basis for them (36, 37).”
p75NTR Mediates Ephrin-A Reverse Signaling Required for Axon Repulsion and Mapping
Lim, Y.-S., McLaughlin, T., Sung, T.-C., Santiago, A., Lee, K., & O’Leary, D. D. M. (2008) · Neuron · doi:10.1016/j.neuron.2008.07.032 · Cited by 210
“…and transmembrane signaling partners in neurons include the transmembrane protein CASPR and the GPI-linked cell adhesion molecule contactin (Peles et al., 1997) and binding of GDNF to the receptor complex formed by the GPI-anchored receptor GFRα1 and the transmembrane protein c-Ret (Jing…”
The Electrophysiological Signature of Spiral Ganglion Neurons
Davis, R., & Crozier, R. (2016) · Springer handbook of auditory research · doi:10.1007/978-1-4939-3031-9_4 · Cited by 4
Recombinant lectin Gg for brain imaging of glycan structure and formation in the CNS node of Ranvier
Tulin, E. K. C., Yoshimura, T., Nakazawa, C., Saito, S., Kanai, K., Kozono, T., Nakakita, S., Tonozuka, T., Ikenaka, K., & Nishikawa, A. (2022) · Journal of Neurochemistry · doi:10.1111/jnc.15695 · Cited by 3
“The paranodal junction, which functions as a barrier limiting clustering of nodal and paranodal proteins, is composed of glial neurofascin 155 that binds to axonal Caspr and Contactin (Boyle et al., 2001; Peles et al., 1997; Tait et al., 2000).”
BackgroundJovanova-Nešić, K., & Shoenfeld, Y. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1381.016 · Cited by 3
Polymorphism of the untranslated regions of the F3/contactin mRNA in the rat nervous system.
Rome, C., Roullot, V., & Couillaud, F. (2005) · Brain Research. Molecular Brain Research · doi:10.1016/j.molbrainres.2005.05.012 · Cited by 3
The Plasma Membrane and the Cell Wall
Sampathkumar, A., Neumetzler, L., & Persson, S. (2010) · Plant cell monographs · doi:10.1007/978-3-642-13431-9_3 · Cited by 3
“1998) as was shown for contactin, which is part of a signal transduction complex that mediates signals between glia and neuron cells in rats (Peles et al. 1997).”
BackgroundIwanaga, S., Gokudan, S., & Mizuguchi, J. (2008) · doi:10.1007/978-4-431-78847-8_31 · Cited by 3
Sima, A. A. F., Zhang, W., & Kamiya, H. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-311-0_8 · Cited by 2
Chapter 24 – Transgenic Models of Nerve Degeneration
Martini, R. (2005) · Elsevier eBooks · doi:10.1016/b978-0-7216-9491-7.50027-2 · Cited by 3
Contactin-1 is a critical neuronal cell surface receptor for perineuronal net structure
Sinha, A., Nickerson, G. A., Bouyain, S., & Matthews, R. T. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108504 · Cited by 5
Sell, L., Zabel, C., Grønborg, S. W., Shi, Q., & Bhat, M. (2025) · Journal of Neuroscience Research · doi:10.1002/jnr.70040 · Cited by 2
“One of the essential proteins in the paranodal region is the contactin-associated protein 1 (also referred to as Caspr1) which is encoded by the Cntnap1 gene (Bhat et al. 2001; Menegoz et al. 1997; Peles et al. 1997).”
Myelin and nodal plasticity modulate action potential conduction in the adult mouse brain
Cullen, C., Pepper, R. E., Clutterbuck, M. T., Pitman, K. A., Oorschot, V., Auderset, L., Tang, A., Ramm, G., Emery, B., Rodger, J., et al. (2019) · bioRxiv · doi:10.1101/726760 · Cited by 2
[Axon and Schwann cells... so far away, so close].
Martin, P.-M., Cifuentes-Diaz, C., Garcia, M., Goutebroze, L., & Girault, J. (2008) · Revue neurologique (Paris) · doi:10.1016/j.neurol.2008.10.003 · Cited by 2
Kostrikov, S., Hjortkjaer, J., Dau, T., Corfas, G., Liberman, L. D., & Liberman, M. (2024) · Hearing Research · doi:10.1016/j.heares.2024.109172 · Cited by 1
MPZ-T124M mouse model replicates human axonopathy and suggest alteration in axo-glia communicationPreprint
Shackleford, G., Marziali, L., Sasaki, Y., Weinstock, N., Rossor, A., Silvestri, N., Wilson, E. R., Hurley, E., Kidd, G., Manohar, S., et al. (2022) · bioRxiv · doi:10.1101/2022.05.09.491190 · Cited by 1
Delgado, P. G., James, R., Browne, E., Meng, J., Umashankar, S., Picón, C., Mazarakis, N., Faisal, A., Howell, O., & Reynolds, R. (2020) · bioRxiv · doi:10.1101/2020.06.10.142281 · Cited by 1
Comunicación entre células gliales y neuronas II. Células gliales que forman mielina
Martínez-Gómez, A. (2014) · Medicina e Investigación · doi:10.1016/s2214-3106(15)30003-0 · Cited by 1
Structure and Function of Myelinated Axons
Buffington, S. A., & Rasband, M. N. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-397265-1.00078-2 · Cited by 2
Functional Domains in Myelinated Axons
Yermakov, L. M., Hong, L. A., Drouet, D. E., Griggs, R. B., & Susuki, K. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9636-7_6 · Cited by 5
Gardiner, D. (2011) · VCU Scholars Compass (Virginia Commonwealth University) · doi:10.25772/8gzz-w709 · Cited by 1
“Contactin-associated protein (Caspr), also called paranodin or NCPI is a type I integral membrane protein (190 kDa) that is highly expressed in the central nervous system (Peles et al., 1997).”
Background3 – Molecular Specializations at the Glia-Axon Interface
Peles, E. (2005) · Elsevier eBooks · doi:10.1016/b978-012738761-1/50004-3 · Cited by 1
Self-citationDing, X., Ogawa, Y., Palfini, V. L., Zhang, W., Anderson, A. P., Gancedo-Lopez, L. L., Liao, Z., Yang, Z., Haddix, S. G., Xing, Y., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.18.745582
“The first molecular description of paranodes and axoglial interactions included the landmark discoveries of Caspr, Contactin, and Neuro-fascin 49,53-56 .”
Kostrikov, S., Hjortkjaer, J., Dau, T., Corfas, G., Liberman, L. D., & Liberman, M. C. (2026) · Hearing Research · doi:10.1016/j.heares.2026.109726
Kostrikov, S., Hjortkjaer, J., Dau, T., Corfas, G., Liberman, L. D., & Liberman, M. (2024) · bioRxiv · doi:10.1101/2024.11.04.621861
“We used a lipophilic fluorophore (Cellmask â ) to label the myelin sheaths and antibodies to Contactin Associated Protein 1 (Caspr) to label the paranodal and juxtaparanodal regions of the nodes of Ranvier (Hossain et al., 2005; Peles et al., 1997).”
Assessment of serum markers in preeclampsia: A prospective study
Çiçek, H., Kuba, A., Uğur, M., Güllü, E., & Tepe, N. (2024) · International Journal of Clinical Biochemistry and Research · doi:10.18231/j.ijcbr.2023.056
Jentzer, A., Taieb, G., Vincent, T., & Devaux, J. (2023) · Revue Francophone des Laboratoires · doi:10.1016/s1773-035x(23)00135-1
Lin, J.-P., Mironova, Y. A., Shrager, P., & Giger, R. (2017) · bioRxiv · doi:10.1101/189563
“A 0334, 1:2000), mouse anti-APC (Calbiochem, OP80, Clone CC1, 1:500), rabbit anti-Caspr (1:1000, (Peles et al., 1997)), mouse anti-Na Channel (1:75, (Rasband et al., 1999)).”
Klingler, E. (2014) · theses.fr (ABES) · doi:10.70675/08960f99zc1c2z47ecz926ez1c3271db22da
“Leur région extracellulaire est composée de différents sousdomaines, incluant un domaine discoidine, plusieurs modules de laminine-G et d’homologie avec l’EGF (Menegoz et al., 1997; Peles et al., 1997).”
BackgroundCharakterisierung von EPB41 - Spleißformen im menschlichen Gehirn
Jacobi, C. (2001) · doi:10.18452/14632
“Peles et al. (1997) zeigten die Interaktion von Contactin mit Neurexin IV, an das p4.”
BackgroundTricellular junction regulation, signaling and scaffolding
Sharifkhodaei, Z. (2017) · doi:10.14288/1.0356610
“Axon-glia interactions and the domain organization of myelinated axons requires neurexin IV/Caspr/Paranodin.”
BackgroundInfluentialMyelin is not required for maintenance of the axon initial segment
Josephson, A. (2013) · doi:10.25772/1qfv-v227
FIZIOLOŠKI I BIOHEMIJSKI ASPEKTI REGENERACIJE KOŠUTICE (Fritillaria meleagris L.) IN VITRO
Beogradu, U., & Petric, M. (2012) · doi:10.2298/bg20120710petric
The Mechanisms Underlying the Effects of C-Peptide on Type 1 Diabetic Neuropathy
Kamiya, H., Zhang, W., & Sima, A. (2012) · Humana Press eBooks · doi:10.1007/978-1-61779-391-2_8
Wang, P.-S. (2011) · doi:10.14288/1.0071812
“Moreover, glial PTP$ binds to a cell recognition complex on neurons, which consist of contactin, Caspr (Peles et al., 1997), and NCAM (Sakurai et al., 1997).”
BackgroundHarris, J. L. (2008) · VCU Scholars Compass (Virginia Commonwealth University) · doi:10.25772/0dqa-d954
“…of the core protein, which is shared by all RPTPβ splice variants, has been shown to bind to the cell surface adhesion molecule F3/contactin (Peles et al., 1995), the transmembrane glycoprotein Caspr/paranodin (Peles et al., 1997), and to the extracellular portion of voltage-activated Na+ channels.”
BackgroundNovel Insights into Schwann Cell Dynamics in Peripheral Nervous System Myelination: a dissertation
Gatto, C. (2004) · doi:10.13028/apvh-cn64
“1, ezrin, radixin, moesin) and SH3 domain (Peles et al., 1997).”
[Paranodal junctions of myelinated fibers: site of anchorage and interactions].
Lubetzki, C., Charles, P., Denisenko‐Nehrbass, N., Barbin, G., & Girault, J. (2003) · médecine/sciences · doi:10.1051/medsci/200319122
Les jonctions paranodales des fibres myélinisées : site d’ancrage, lieu d’interactions
Lubetzki, C., Charles, P., Denisenko-Nehrbass, N., Barbin, G., & Girault, J.-A. (2003) · doi:10.7202/000752ar
Metadata
- Authors
- Peles, E., Nativ, M., Lustig, M., Grumet, M., Schilling, J., Martinez, R., Plowman, G. D., & Schlessinger, J.
- Affiliations
- NYU Langone Health (US)
- Corresponding author
- Schlessinger, Joseph
- Venue
- The EMBO Journal
- Published
- 1997-03-01
- Volume
- 16
- Issue
- 5
- Pages
- 978-988
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1169698
- OpenAlex
- W2098584548
- Cited by
- 400
- References
- 0
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 6 · 2022: 9 · 2021: 6 · 2020: 13 · 2019: 8 · 2018: 9 · 2017: 9 · 2016: 10 · 2015: 8 · 2014: 15 · 2013: 11 · 2012: 12
- FWCI
- 9.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns021629-11)
- National Institute of Neurological Disorders and Stroke (NS21629)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Caspr, contactin, epidermal growth factor-like repeats, SH3 domain binding, neurite outgrowth, intracellular signaling, rat brain
- MeSH terms
- Amino Acid Sequence, Animals, Cell Membrane, Cloning, Molecular, Humans, Immunohistochemistry, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Protein Binding, Receptors, Cell Surface, Recombinant Fusion Proteins, RNA, Messenger, Tumor Cells, Cultured, Blotting, Western, Signal Transduction, Cell Adhesion Molecules, Neuronal, Gene Expression, Sequence Alignment, src Homology Domains, Rats, Contactins
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