Skip to main content

The interaction between L1-type proteins and ankyrins - a master switch for L1-type CAM function


L1-type cell adhesion molecules (CAMs) are important mediators of neural differentiation, including axonal outgrowth and pathfinding and also of synapse formation and maintenance. In addition, their interactions with cytoskeletal components are highly conserved and regulated. How these different aspects of CAM functionality relate to each other is not well understood. Based on results from our and other laboratories we propose that ankyrin-binding to L1-type CAMs provides a master switch. The interaction with ankyrins directs L1-type adhesive proteins into different functional contexts, either ankyrin-independent functions, such as neurite outgrowth and axonal pathfinding or into ankyrin-dependent functions, such as L1’s role at axon initial segments (AIS), paranodal regions, synapses and in dendrites.



axon initial segments


cell adhesion molecule


epidermal growth factor receptor


fibroblast growth factor receptor


giant fiber


glycosyl phosphoinositol


neuromuscular junction


receptor tyrosine kinase


synapse-associated proteins


tergotrochanteral motorneuron


ventral unpaired median


  1. Hortsch, M. Structural and functional evolution of the L1-family: Are four adhesion molecules better than one? Mol. Cell. Neurosci. 15 (2000) 1–10.

    PubMed  Article  CAS  Google Scholar 

  2. Hortsch, M. and Margolis, B. Septate and paranodal junctions: Kissing cousins. Trends Cell. Biol. 13 (2003) 557–561.

    PubMed  Article  CAS  Google Scholar 

  3. Panicker, A.K., Buhusi, M., Thelen, K. and Maness, P.F. Cellular signalling mechanisms of neural cell adhesion molecules. Front. Biosci. 8 (2003) D900–911.

    PubMed  Article  CAS  Google Scholar 

  4. Godenschwege, T.A., Kristiansen, L.V., Uthaman, S.B., Hortsch, M. and Murphey, R.K. A conserved role for Drosophila Neuroglian and human L1-CAM in central-synapse formation. Curr. Biol. 16 (2006) 12–23.

    PubMed  Article  CAS  Google Scholar 

  5. Ango, F., di Cristo, G., Higashiyama, H., Bennett, V., Wu, P. and Huang, Z.J. Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at purkinje axon initial segment. Cell 119 (2004) 257–272.

    PubMed  Article  CAS  Google Scholar 

  6. Triana-Baltzer, G.B., Liu, Z. and Berg, D.K. Pre- and postsynaptic actions of L1-CAM in nicotinic pathways. Mol. Cell. Neurosci. 33 (2006) 214–226.

    PubMed  Article  CAS  Google Scholar 

  7. Hortsch, M. The L1 family of neural cell adhesion molecules: Old proteins performing new tricks. Neuron 17 (1996) 587–593.

    PubMed  Article  CAS  Google Scholar 

  8. Davis, J.Q., McLaughlin, T. and Bennett, V. Ankyrin-binding proteins related to nervous system cell adhesion molecules: candidates to provide transmembrane and intercellular connections in adult brain. J. Cell. Biol. 121 (1993) 121–133.

    PubMed  Article  CAS  Google Scholar 

  9. Davis, J.Q. and Bennett, V. Ankyrin binding activity shared by the neurofascin/L1/NrCAM family of nervous system cell adhesion molecules. J. Biol. Chem. 269 (1994) 27163–27166.

    PubMed  CAS  Google Scholar 

  10. Dubreuil, R.R., MacVicar, G., Dissanayake, S., Liu, C., Homer, D. and Hortsch, M. Neuroglian-mediated cell adhesion induces assembly of the membrane skeleton at cell contact sites. J. Cell. Biol. 133 (1996) 647–655.

    PubMed  Article  CAS  Google Scholar 

  11. Malhotra, J.D., Tsiotra, P., Karagogeos, D. and Hortsch, M. Cis-activation of L1-mediated ankyrin recruitment by TAG-1 homophilic cell adhesion. J. Biol. Chem. 273 (1998) 33354–33359.

    PubMed  Article  CAS  Google Scholar 

  12. Hortsch, M., Homer, D., Malhotra, J.D., Chang, S., Frankel, J., Jefford, G. and Dubreuil, R.R. Structural requirements for “outside-in” and “inside-out” signaling by Drosophila neuroglian, a member of the L1 family of cell adhesion molecules. J. Cell. Biol. 142 (1998) 251–261.

    PubMed  Article  CAS  Google Scholar 

  13. Garver, T.D., Ren, Q., Tuvia, S. and Bennett, V. Tyrosine phosphorylation at a site highly conserved in the L1 family of cell adhesion molecules abolishes ankyrin binding and increases lateral mobility of neurofascin. J. Cell. Biol. 137 (1997) 703–714.

    PubMed  Article  CAS  Google Scholar 

  14. Bouley, M., Tian, M.-Z., Paisley, K., Shen, Y.-C., Malhotra, J.D. and Hortsch, M. The L1-type cell adhesion molecule neuroglian influences the stability of neural ankyrin in the Drosophila embryo but not its axonal localization. J. Neurosci. 20 (2000) 4515–4523.

    PubMed  CAS  Google Scholar 

  15. Tuvia, S., Garver, T.D. and Bennett, V. The phosphorylation state of the FIGQY tyrosine of neurofascin determines ankyrin-binding activity and patterns of cell segregation. Proc. Natl. Acad. Sci. USA 94 (1997) 12957–12962.

    PubMed  Article  CAS  Google Scholar 

  16. Kizhatil, K., Wu, Y.X., Sen, A. and Bennett, V. A new activity of doublecortin in recognition of the phospho-FIGQY tyrosine in the cytoplasmic domain of neurofascin. J. Neurosci. 22 (2002) 7948–7958.

    PubMed  CAS  Google Scholar 

  17. Jenkins, S.M., Kizhatil, K., Kramarcy, N.R., Sen, A., Sealock, R. and Bennett, V. FIGQY phosphorylation defines discrete populations of L1 cell adhesion molecules at sites of cell-cell contact and in migrating neurons. J. Cell Sci. 114 (2001) 3823–3835.

    PubMed  CAS  Google Scholar 

  18. Whittard, J.D., Sakurai, T., Cassella, M.R., Gazdoiu, M. and Felsenfeld, D.P. MAP kinase pathway-dependent phosphorylation of the L1-CAM ankyrin-binding site regulates neuronal growth. Mol. Biol. Cell (2006).

  19. Gil, O.D., Sakurai, T., Bradley, A.E., Fink, M.Y., Cassella, M.R., Kuo, J.A. and Felsenfeld, D.P. Ankyrin binding mediates L1CAM interactions with static components of the cytoskeleton and inhibits retrograde movement of L1CAM on the cell surface. J. Cell. Biol. 162 (2003) 719–730.

    PubMed  Article  CAS  Google Scholar 

  20. Chen, L., Ong, B. and Bennett, V. LAD-1, the Caenorhabditis elegans L1CAM homologue, participates in embryonic and gonadal morphogenesis and is a substrate for fibroblast growth factor receptor pathway-dependent phosphotyrosine-based signaling. J. Cell. Biol. 154 (2001) 841–856.

    PubMed  Article  CAS  Google Scholar 

  21. Bennett, V. and Baines, A.J. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. Physiol. Rev. 81 (2001) 1353–1392.

    PubMed  CAS  Google Scholar 

  22. Mohler, P.J., Gramolini, A.O. and Bennett, V. Ankyrins. J. Cell Sci. 115 (2002) 1565–1566.

    PubMed  CAS  Google Scholar 

  23. Otsuka, A.J., Franco, R., Yang, B., Shim, K.H., Tang, L.Z., Zhang, Y.Y., Boontrakulpoontawee, P., Jeyaprakash, A., Hedgecock, E., Wheaton, V.I. and Sobery, A. An ankyrin-related gene (unc-44) is necessary for proper axonal guidance in Caenorhabditis elegans. J. Cell. Biol. 129 (1995) 1081–1092.

    PubMed  Article  CAS  Google Scholar 

  24. Dubreuil, R.R. and Yu, J.-Q. Ankyrin and beta-spectrin accumulate independently of alpha-spectrin in Drosophila. Proc. Natl. Acad. Sci. USA 91 (1994) 10285–10289.

    PubMed  Article  CAS  Google Scholar 

  25. Koch, I., Schwarz, H., Beuchle, D., Goellner, B., Langegger, M. and Aberle, H. Drosophila ankyrin 2 is required for synaptic stability. Neuron 58 (2008) 210–222.

    PubMed  Article  CAS  Google Scholar 

  26. Hortsch, M., Paisley, K.L., Tian, M.Z., Qian, M., Bouley, M. and Chandler, R. The axonal localization of large Drosophila ankyrin2 protein isoforms is essential for neuronal functionality. Mol. Cell. Neurosci. 20 (2002) 43–55.

    PubMed  Article  CAS  Google Scholar 

  27. Pielage, J., Cheng, L., Fetter, R.D., Carlton, P.M., Sedat, J.W. and Davis, G.W. A presynaptic giant ankyrin stabilizes the NMJ through regulation of presynaptic microtubules and transsynaptic cell adhesion. Neuron 58 (2008) 195–209.

    PubMed  Article  CAS  Google Scholar 

  28. Otsuka, A.J., Boontrakulpoontawee, P., Rebeiz, N., Domanus, M., Otsuka, D., Velamparampil, N., Chan, S., Vande Wyngaerde, M., Campagna, S. and Cox, A. Novel UNC-44 AO13 ankyrin is required for axonal guidance in C. elegans, contains six highly repetitive STEP blocks separated by seven potential transmembrane domains, and is localized to neuronal processes and the periphery of neural cell bodies. J. Neurobiol. 50 (2002) 333–349.

    PubMed  Article  CAS  Google Scholar 

  29. Kordeli, E., Davis, J., Trapp, B. and Bennett, V. An isoform of ankyrin is localized at nodes of Ranvier in myelinated axons of central and peripheral nerves. J. Cell. Biol. 110 (1990) 1341–1352.

    PubMed  Article  CAS  Google Scholar 

  30. Islam, R., Kristansen, L.V., Romani, S., Garcia-Alonso, L. and Hortsch, M. Activation of EGF receptor kinase by L1-mediated homophilic cell interactions. Mol. Biol. Cell 15 (2004) 1509–1518.

    Article  Google Scholar 

  31. Garcia-Alonso, L., Romani, S. and Jimenez, F. The EGF and FGF receptors mediate neuroglian function to control growth cone decisions during sensory axon guidance in Drosophila. Neuron 28 (2000) 741–752.

    PubMed  Article  CAS  Google Scholar 

  32. Kristiansen, L.V., Velasquez, E., Romani, S., Baars, S., Berezin, V., Bock, E., Hortsch, M. and Garcia-Alonso, L. Genetic analysis of an overlapping functional requirement for L1- and NCAM-type proteins during sensory axon guidance in Drosophila. Mol. Cell. Neurosci. 28 (2005) 141–152.

    PubMed  Article  CAS  Google Scholar 

  33. Nishimura, K., Yoshihara, F., Tojima, T., Ooashi, N., Yoon, W., Mikoshiba, K., Bennett, V. and Kamiguchi, H. L1-dependent neuritogenesis involves ankyrinB that mediates L1-CAM coupling with retrograde actin flow. J. Cell. Biol. 163 (2003) 1077–1088.

    PubMed  Article  CAS  Google Scholar 

  34. Davey, F., Hill, M., Falk, J., Sans, N. and Gunn-Moore, F.J. Synapse associated protein 102 is a novel binding partner to the cytoplasmic terminus of neurone-glial related cell adhesion molecule. J. Neurochem. 94 (2005) 1243–1253.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Michael Hortsch.

Additional information

The content of this Mini review was first presented in a shortened form at the 12th Mejbaum-Katzenellenbogen Seminar “Membrane Skeleton. Recent Advances and Future Research Directions”, June 15–18, 2008, Zakopane, Poland

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hortsch, M., Nagaraj, K. & Godenschwege, T.A. The interaction between L1-type proteins and ankyrins - a master switch for L1-type CAM function. Cell Mol Biol Lett 14, 57–69 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Key words

  • Cell adhesion
  • Ankyrins
  • Membrane skeleton
  • Tyrosine phosphorylation
  • Neurite outgrowth
  • Neuromuscular junction
  • Synapse
  • Synaptogenesis
  • Drosophila