Skip to main content
NCBI home page
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2003 Apr 29;358(1432):749–756. doi: 10.1098/rstb.2002.1256

Cadherins and synaptic plasticity: activity-dependent cyclin-dependent kinase 5 regulation of synaptic beta-catenin-cadherin interactions.

Erin M Schuman 1, Sachiko Murase 1
PMCID: PMC1693152  PMID: 12740122

Abstract

Cyclin-dependent kinase 5 (Cdk5)/p35 kinase activity is known to decrease the affinity of beta-catenin for cadherin in developing cortical neurons. Our recent work demonstrated that depolarization causes an increased affinity between beta-catenin and cadherin. Here, we examine whether Cdk5/p35 regulates beta-catenin-cadherin affinity in response to neural activity. In hippocampal neurons depolarization caused a significant decrease in Cdk5 kinase activity, without changing the protein levels of either Cdk5 or p35, suggesting that the proteasome pathway is not involved. Decreasing Cdk5 kinase activity with the inhibitor roscovitine increased the amount of beta-catenin that was co-immunoprecipitated with cadherin. Inhibiting Cdk5 activity also resulted in a redistribution of EGFP-beta-catenin from the dendritic shaft to the spines, where cadherins are highly concentrated. The redistribution of beta-catenin induced by roscovitine is similar to that induced by depolarization. Interestingly, the redistribution induced by the Cdk5 inhibitor was completely blocked by either a tyrosine phosphatase inhibitor, orthovanadate or by point mutations of beta-catenin Tyr-654 to Glu or Phe. Immunoprecipitation studies further revealed that roscovitine increases the affinity of the wild-type, but not mutated, EGFP-beta-catenin for cadherin. These results suggest that Cdk5 activity regulates the affinity of beta-catenin for cadherin by changing the phosphorylation level of beta-catenin Tyr-654.

Full Text

The Full Text of this article is available as a PDF (366.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Balsamo J., Arregui C., Leung T., Lilien J. The nonreceptor protein tyrosine phosphatase PTP1B binds to the cytoplasmic domain of N-cadherin and regulates the cadherin-actin linkage. J Cell Biol. 1998 Oct 19;143(2):523–532. doi: 10.1083/jcb.143.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Balsamo J., Leung T., Ernst H., Zanin M. K., Hoffman S., Lilien J. Regulated binding of PTP1B-like phosphatase to N-cadherin: control of cadherin-mediated adhesion by dephosphorylation of beta-catenin. J Cell Biol. 1996 Aug;134(3):801–813. doi: 10.1083/jcb.134.3.801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Behrens J., Vakaet L., Friis R., Winterhager E., Van Roy F., Mareel M. M., Birchmeier W. Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. J Cell Biol. 1993 Feb;120(3):757–766. doi: 10.1083/jcb.120.3.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benson D. L., Tanaka H. N-cadherin redistribution during synaptogenesis in hippocampal neurons. J Neurosci. 1998 Sep 1;18(17):6892–6904. doi: 10.1523/JNEUROSCI.18-17-06892.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bonvini P., An W. G., Rosolen A., Nguyen P., Trepel J., Garcia de Herreros A., Dunach M., Neckers L. M. Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription. Cancer Res. 2001 Feb 15;61(4):1671–1677. [PubMed] [Google Scholar]
  6. Bozdagi O., Shan W., Tanaka H., Benson D. L., Huntley G. W. Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. Neuron. 2000 Oct;28(1):245–259. doi: 10.1016/s0896-6273(00)00100-8. [DOI] [PubMed] [Google Scholar]
  7. Cantley L. C., Jr, Josephson L., Warner R., Yanagisawa M., Lechene C., Guidotti G. Vanadate is a potent (Na,K)-ATPase inhibitor found in ATP derived from muscle. J Biol Chem. 1977 Nov 10;252(21):7421–7423. [PubMed] [Google Scholar]
  8. Chae T., Kwon Y. T., Bronson R., Dikkes P., Li E., Tsai L. H. Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron. 1997 Jan;18(1):29–42. doi: 10.1016/s0896-6273(01)80044-1. [DOI] [PubMed] [Google Scholar]
  9. Fannon A. M., Colman D. R. A model for central synaptic junctional complex formation based on the differential adhesive specificities of the cadherins. Neuron. 1996 Sep;17(3):423–434. doi: 10.1016/s0896-6273(00)80175-0. [DOI] [PubMed] [Google Scholar]
  10. Fischer André, Sananbenesi Farahnaz, Schrick Christina, Spiess Joachim, Radulovic Jelena. Cyclin-dependent kinase 5 is required for associative learning. J Neurosci. 2002 May 1;22(9):3700–3707. doi: 10.1523/JNEUROSCI.22-09-03700.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hamaguchi M., Matsuyoshi N., Ohnishi Y., Gotoh B., Takeichi M., Nagai Y. p60v-src causes tyrosine phosphorylation and inactivation of the N-cadherin-catenin cell adhesion system. EMBO J. 1993 Jan;12(1):307–314. doi: 10.1002/j.1460-2075.1993.tb05658.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hazan R. B., Norton L. The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton. J Biol Chem. 1998 Apr 10;273(15):9078–9084. doi: 10.1074/jbc.273.15.9078. [DOI] [PubMed] [Google Scholar]
  13. Hirano S., Kimoto N., Shimoyama Y., Hirohashi S., Takeichi M. Identification of a neural alpha-catenin as a key regulator of cadherin function and multicellular organization. Cell. 1992 Jul 24;70(2):293–301. doi: 10.1016/0092-8674(92)90103-j. [DOI] [PubMed] [Google Scholar]
  14. Husi H., Ward M. A., Choudhary J. S., Blackstock W. P., Grant S. G. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci. 2000 Jul;3(7):661–669. doi: 10.1038/76615. [DOI] [PubMed] [Google Scholar]
  15. Kesavapany S., Lau K. F., McLoughlin D. M., Brownlees J., Ackerley S., Leigh P. N., Shaw C. E., Miller C. C. p35/cdk5 binds and phosphorylates beta-catenin and regulates beta-catenin/presenilin-1 interaction. Eur J Neurosci. 2001 Jan;13(2):241–247. [PubMed] [Google Scholar]
  16. Kwon Y. T., Gupta A., Zhou Y., Nikolic M., Tsai L. H. Regulation of N-cadherin-mediated adhesion by the p35-Cdk5 kinase. Curr Biol. 2000 Apr 6;10(7):363–372. doi: 10.1016/s0960-9822(00)00411-5. [DOI] [PubMed] [Google Scholar]
  17. Kypta R. M., Su H., Reichardt L. F. Association between a transmembrane protein tyrosine phosphatase and the cadherin-catenin complex. J Cell Biol. 1996 Sep;134(6):1519–1529. doi: 10.1083/jcb.134.6.1519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Manabe T., Togashi H., Uchida N., Suzuki S. C., Hayakawa Y., Yamamoto M., Yoda H., Miyakawa T., Takeichi M., Chisaka O. Loss of cadherin-11 adhesion receptor enhances plastic changes in hippocampal synapses and modifies behavioral responses. Mol Cell Neurosci. 2000 Jun;15(6):534–546. doi: 10.1006/mcne.2000.0849. [DOI] [PubMed] [Google Scholar]
  19. Matsuyoshi N., Hamaguchi M., Taniguchi S., Nagafuchi A., Tsukita S., Takeichi M. Cadherin-mediated cell-cell adhesion is perturbed by v-src tyrosine phosphorylation in metastatic fibroblasts. J Cell Biol. 1992 Aug;118(3):703–714. doi: 10.1083/jcb.118.3.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Meijer L., Borgne A., Mulner O., Chong J. P., Blow J. J., Inagaki N., Inagaki M., Delcros J. G., Moulinoux J. P. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem. 1997 Jan 15;243(1-2):527–536. doi: 10.1111/j.1432-1033.1997.t01-2-00527.x. [DOI] [PubMed] [Google Scholar]
  21. Murase S., Schuman E. M. The role of cell adhesion molecules in synaptic plasticity and memory. Curr Opin Cell Biol. 1999 Oct;11(5):549–553. doi: 10.1016/s0955-0674(99)00019-8. [DOI] [PubMed] [Google Scholar]
  22. Murase Sachiko, Mosser Eric, Schuman Erin M. Depolarization drives beta-Catenin into neuronal spines promoting changes in synaptic structure and function. Neuron. 2002 Jul 3;35(1):91–105. doi: 10.1016/s0896-6273(02)00764-x. [DOI] [PubMed] [Google Scholar]
  23. Nagafuchi A., Ishihara S., Tsukita S. The roles of catenins in the cadherin-mediated cell adhesion: functional analysis of E-cadherin-alpha catenin fusion molecules. J Cell Biol. 1994 Oct;127(1):235–245. doi: 10.1083/jcb.127.1.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nikolic M., Chou M. M., Lu W., Mayer B. J., Tsai L. H. The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature. 1998 Sep 10;395(6698):194–198. doi: 10.1038/26034. [DOI] [PubMed] [Google Scholar]
  25. Nikolic M., Dudek H., Kwon Y. T., Ramos Y. F., Tsai L. H. The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev. 1996 Apr 1;10(7):816–825. doi: 10.1101/gad.10.7.816. [DOI] [PubMed] [Google Scholar]
  26. Ozawa M., Kemler R. Altered cell adhesion activity by pervanadate due to the dissociation of alpha-catenin from the E-cadherin.catenin complex. J Biol Chem. 1998 Mar 13;273(11):6166–6170. doi: 10.1074/jbc.273.11.6166. [DOI] [PubMed] [Google Scholar]
  27. Ozawa M., Ringwald M., Kemler R. Uvomorulin-catenin complex formation is regulated by a specific domain in the cytoplasmic region of the cell adhesion molecule. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4246–4250. doi: 10.1073/pnas.87.11.4246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Pathre P., Arregui C., Wampler T., Kue I., Leung T. C., Lilien J., Balsamo J. PTP1B regulates neurite extension mediated by cell-cell and cell-matrix adhesion molecules. J Neurosci Res. 2001 Jan 15;63(2):143–150. doi: 10.1002/1097-4547(20010115)63:2<143::AID-JNR1006>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]
  29. Phillips G. R., Huang J. K., Wang Y., Tanaka H., Shapiro L., Zhang W., Shan W. S., Arndt K., Frank M., Gordon R. E. The presynaptic particle web: ultrastructure, composition, dissolution, and reconstitution. Neuron. 2001 Oct 11;32(1):63–77. doi: 10.1016/s0896-6273(01)00450-0. [DOI] [PubMed] [Google Scholar]
  30. Rudolph B., Saffrich R., Zwicker J., Henglein B., Müller R., Ansorge W., Eilers M. Activation of cyclin-dependent kinases by Myc mediates induction of cyclin A, but not apoptosis. EMBO J. 1996 Jun 17;15(12):3065–3076. [PMC free article] [PubMed] [Google Scholar]
  31. Seargeant L. E., Stinson R. A. Inhibition of human alkaline phosphatases by vanadate. Biochem J. 1979 Jul 1;181(1):247–250. doi: 10.1042/bj1810247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sommers C. L., Gelmann E. P., Kemler R., Cowin P., Byers S. W. Alterations in beta-catenin phosphorylation and plakoglobin expression in human breast cancer cells. Cancer Res. 1994 Jul 1;54(13):3544–3552. [PubMed] [Google Scholar]
  33. Stoppini L., Buchs P. A., Muller D. A simple method for organotypic cultures of nervous tissue. J Neurosci Methods. 1991 Apr;37(2):173–182. doi: 10.1016/0165-0270(91)90128-m. [DOI] [PubMed] [Google Scholar]
  34. Takeichi M. Cadherins: a molecular family important in selective cell-cell adhesion. Annu Rev Biochem. 1990;59:237–252. doi: 10.1146/annurev.bi.59.070190.001321. [DOI] [PubMed] [Google Scholar]
  35. Tanaka H., Shan W., Phillips G. R., Arndt K., Bozdagi O., Shapiro L., Huntley G. W., Benson D. L., Colman D. R. Molecular modification of N-cadherin in response to synaptic activity. Neuron. 2000 Jan;25(1):93–107. doi: 10.1016/s0896-6273(00)80874-0. [DOI] [PubMed] [Google Scholar]
  36. Tang L., Hung C. P., Schuman E. M. A role for the cadherin family of cell adhesion molecules in hippocampal long-term potentiation. Neuron. 1998 Jun;20(6):1165–1175. doi: 10.1016/s0896-6273(00)80497-3. [DOI] [PubMed] [Google Scholar]
  37. Togashi Hideru, Abe Kentaro, Mizoguchi Akira, Takaoka Kanna, Chisaka Osamu, Takeichi Masatoshi. Cadherin regulates dendritic spine morphogenesis. Neuron. 2002 Jul 3;35(1):77–89. doi: 10.1016/s0896-6273(02)00748-1. [DOI] [PubMed] [Google Scholar]
  38. Tomizawa Kazuhito, Ohta Jun, Matsushita Masayuki, Moriwaki Akiyoshi, Li Sheng-Tian, Takei Kohji, Matsui Hideki. Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity. J Neurosci. 2002 Apr 1;22(7):2590–2597. doi: 10.1523/JNEUROSCI.22-07-02590.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Uchida N., Honjo Y., Johnson K. R., Wheelock M. J., Takeichi M. The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones. J Cell Biol. 1996 Nov;135(3):767–779. doi: 10.1083/jcb.135.3.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zukerberg L. R., Patrick G. N., Nikolic M., Humbert S., Wu C. L., Lanier L. M., Gertler F. B., Vidal M., Van Etten R. A., Tsai L. H. Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron. 2000 Jun;26(3):633–646. doi: 10.1016/s0896-6273(00)81200-3. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES