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NeuroMolecular Medicine
Erschienen in: NeuroMolecular Medicine 1/2015

01.03.2015 | Original Paper

Sumoylation of p35 Modulates p35/Cyclin-Dependent Kinase (Cdk) 5 Complex Activity

verfasst von: Anja Büchner, Petranka Krumova, Sundar Ganesan, Mathias Bähr, Katrin Eckermann, Jochen H. Weishaupt

Erschienen in: NeuroMolecular Medicine | Ausgabe 1/2015

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Abstract

Cyclin-dependent kinase (Cdk) 5 is critical for central nervous system development and neuron-specific functions including neurite outgrowth as well as synaptic function and plasticity. Cdk5 activity requires association with one of the two regulatory subunits, called p35 and p39. p35 redistribution as well as misregulation of Cdk5 activity is followed by cell death in several models of neurodegeneration. Posttranslational protein modification by small ubiquitin-related modifier (SUMO) proteins (sumoylation) has emerged as key regulator of protein targeting and protein/protein interaction. Under cell-free in vitro conditions, we found p35 covalently modified by SUMO1. Using both biochemical and FRET-/FLIM-based approaches, we demonstrated that SUMO2 is robustly conjugated to p35 in cells and identified the two major SUMO acceptor lysines in p35, K246 and K290. Furthermore, different degrees of oxidative stress resulted in differential p35 sumoylation, linking oxidative stress that is encountered in neurodegenerative diseases to the altered activity of Cdk5. Functionally, sumoylation of p35 increased the activity of the p35/Cdk5 complex. We thus identified a novel neuronal SUMO target and show that sumoylation is a likely candidate mechanism for the rapid modulation of p35/Cdk5 activity in physiological situations as well as in disease.
Literatur
Amor, S., Peferoen, L. A., Vogel, D. Y., Breur, M., van der Valk, P., Baker, D., et al. (2014). Inflammation in neurodegenerative diseases–an update. Immunology, 142(2), 151–166.CrossRefPubMed
Asada, A., Yamamoto, N., Gohda, M., Saito, T., Hayashi, N., & Hisanaga, S. (2008). Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cyclin-dependent kinase 5 complexes. Journal of Neurochemistry, 106(3), 1325–1336.CrossRefPubMed
Bernier-Villamor, V., Sampson, D. A., Matunis, M. J., & Lima, C. D. (2002). Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell, 108(3), 345–356.CrossRefPubMed
Bossis, G., & Melchior, F. (2006). Regulation of SUMOylation by reversible oxidation of SUMO conjugating enzymes. Molecular Cell, 21(3), 349–357.CrossRefPubMed
Chae, T., Kwon, Y. T., Bronson, R., Dikkes, P., Li, E., & Tsai, L. H. (1997). Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron, 18(1), 29–42.CrossRefPubMed
Choe, E. A., Liao, L., Zhou, J. Y., Cheng, D., Duong, D. M., Jin, P., et al. (2007). Neuronal morphogenesis is regulated by the interplay between cyclin-dependent kinase 5 and the ubiquitin ligase mind bomb 1. Journal of Neuroscience, 27(35), 9503–9512.CrossRefPubMed
Day, R. N., Booker, C. F., & Periasamy, A. (2008). Characterization of an improved donor fluorescent protein for Forster resonance energy transfer microscopy. Journal of Biomedial Optics, 13(3), 031203.CrossRef
Desterro, J. M., Rodriguez, M. S., Kemp, G. D., & Hay, R. T. (1999). Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. Journal of Biological Chemistry, 274(15), 10618–10624.CrossRefPubMed
Dhavan, R., & Tsai, L. H. (2001). A decade of CDK5. Nature Reviews Molecular Cell Biology, 2(10), 749–759.CrossRefPubMed
Feligioni, M., & Nistico, R. (2013). SUMO: a (oxidative) stressed protein. Neuromolecular Medicine, 15(4), 707–719.CrossRefPubMed
Fu, X., Choi, Y. K., Qu, D., Yu, Y., Cheung, N. S., & Qi, R. Z. (2006). Identification of nuclear import mechanisms for the neuronal Cdk5 activator. Journal of Biological Chemistry, 281(51), 39014–39021.CrossRefPubMed
Gill, G. (2004). SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes & Development, 18(17), 2046–2059.CrossRef
Golebiowski, F., Matic, I., Tatham, M. H., Cole, C., Yin, Y., Nakamura, A., et al. (2009). System-wide changes to SUMO modifications in response to heat shock. Science Signaling, 2(72), ra24.
Gong, L., Millas, S., Maul, G. G., & Yeh, E. T. (2000). Differential regulation of sentrinized proteins by a novel sentrin-specific protease. Journal of Biological Chemistry, 275(5), 3355–3359.CrossRefPubMed
Halliwell, B., Clement, M. V., & Long, L. H. (2000). Hydrogen peroxide in the human body. FEBS Letters, 486(1), 10–13.CrossRefPubMed
Hecker, C. M., Rabiller, M., Haglund, K., Bayer, P., & Dikic, I. (2006). Specification of SUMO1- and SUMO2-interacting motifs. Journal of Biological Chemistry, 281(23), 16117–16127.CrossRefPubMed
Hsiao, K., Bozdagi, O., & Benson, D. L. (2014). Axonal cap-dependent translation regulates presynaptic p35. Developmental Neurobiology, 74(3), 351–364.CrossRefPubMed
Jaffray, E. G., & Hay, R. T. (2006). Detection of modification by ubiquitin-like proteins. Methods, 38(1), 35–38.CrossRefPubMed
Kim, E. T., Kim, K. K., Matunis, M. J., & Ahn, J. H. (2009). Enhanced SUMOylation of proteins containing a SUMO-interacting motif by SUMO-Ubc9 fusion. Biochemical and Biophysical Research Communications, 388(1), 41–45.CrossRefPubMed
Krumova, P., Meulmeester, E., Garrido, M., Tirard, M., Hsiao, H. H., Bossis, G., et al. (2011). Sumoylation inhibits alpha-synuclein aggregation and toxicity. Journal of Cell Biology, 194(1), 49–60.CrossRefPubMedCentralPubMed
Krumova, P., & Weishaupt, J. H. (2013). Sumoylation in neurodegenerative diseases. Cellular and Molecular Life Sciences, 70(12), 2123–2138.CrossRefPubMed
Li, Z., David, G., Hung, K. W., DePinho, R. A., Fu, A. K., & Ip, N. Y. (2004). Cdk5/p35 phosphorylates mSds3 and regulates mSds3-mediated repression of transcription. Journal of Biological Chemistry, 279(52), 54438–54444.CrossRefPubMed
Macauley, M. S., Errington, W. J., Scharpf, M., Mackereth, C. D., Blaszczak, A. G., Graves, B. J., et al. (2006). Beads-on-a-string, characterization of ETS-1 sumoylated within its flexible N-terminal sequence. Journal of Biological Chemistry, 281(7), 4164–4172.CrossRefPubMed
Mahajan, R., Delphin, C., Guan, T., Gerace, L., & Melchior, F. (1997). A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell, 88(1), 97–107.CrossRefPubMed
Matunis, M. J., Coutavas, E., & Blobel, G. (1996). A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. Journal of Cell Biology, 135(6 Pt 1), 1457–1470.CrossRefPubMed
Mukhopadhyay, D., & Dasso, M. (2007). Modification in reverse: the SUMO proteases. Trends in Biochemical Sciences, 32(6), 286–295.CrossRefPubMed
Nagai, T., Ibata, K., Park, E. S., Kubota, M., Mikoshiba, K., & Miyawaki, A. (2002). A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications. Nature Biotechnology, 20(1), 87–90.CrossRefPubMed
Nguyen, M. D., Lariviere, R. C., & Julien, J. P. (2001). Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions. Neuron, 30(1), 135–147.CrossRefPubMed
Nikolic, M., Dudek, H., Kwon, Y. T., Ramos, Y. F., & Tsai, L. H. (1996). The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes & Development, 10(7), 816–825.CrossRef
O’Hare, M. J., Kushwaha, N., Zhang, Y., Aleyasin, H., Callaghan, S. M., Slack, R. S., et al. (2005). Differential roles of nuclear and cytoplasmic cyclin-dependent kinase 5 in apoptotic and excitotoxic neuronal death. Journal of Neuroscience, 25(39), 8954–8966.CrossRefPubMed
Osuga, H., Osuga, S., Wang, F., Fetni, R., Hogan, M. J., Slack, R. S., et al. (2000). Cyclin-dependent kinases as a therapeutic target for stroke. Proceedings of the National Academy of Sciences USA, 97(18), 10254–10259.CrossRef
Patrick, G. N., Zhou, P., Kwon, Y. T., Howley, P. M., & Tsai, L. H. (1998). p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway. Journal of Biological Chemistry, 273(37), 24057–24064.CrossRefPubMed
Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., & Tsai, L. H. (1999). Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature, 402(6762), 615–622.CrossRefPubMed
Patzke, H., & Tsai, L. H. (2002). Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29. Journal of Biological Chemistry, 277(10), 8054–8060.CrossRefPubMed
Poon, R. Y., Lew, J., & Hunter, T. (1997). Identification of functional domains in the neuronal Cdk5 activator protein. Journal of Biological Chemistry, 272(9), 5703–5708.CrossRefPubMed
Sahlgren, C. M., Pallari, H. M., He, T., Chou, Y. H., Goldman, R. D., & Eriksson, J. E. (2006). A nestin scaffold links Cdk5/p35 signaling to oxidant-induced cell death. EMBO Journal, 25(20), 4808–4819.CrossRefPubMedCentralPubMed
Saitoh, H., & Hinchey, J. (2000). Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. Journal of Biological Chemistry, 275(9), 6252–6258.CrossRefPubMed
Sapetschnig, A., Rischitor, G., Braun, H., Doll, A., Schergaut, M., Melchior, F., et al. (2002). Transcription factor Sp3 is silenced through SUMO modification by PIAS1. EMBO Journal, 21(19), 5206–5215.CrossRefPubMedCentralPubMed
Shea, T. B., Zheng, Y. L., Ortiz, D., & Pant, H. C. (2004). Cyclin-dependent kinase 5 increases perikaryal neurofilament phosphorylation and inhibits neurofilament axonal transport in response to oxidative stress. Journal of Neuroscience Research, 76(6), 795–800.CrossRefPubMed
Shin, E. J., Shin, H. M., Nam, E., Kim, W. S., Kim, J. H., Oh, B. H., et al. (2012). DeSUMOylating isopeptidase: a second class of SUMO protease. EMBO Reports, 13(4), 339–346.CrossRefPubMedCentralPubMed
Shukla, V., Mishra, S. K., & Pant, H. C. (2011). Oxidative stress in neurodegeneration. Advance Pharmacology Science, 2011, 572634.
Smith, P. D., Crocker, S. J., Jackson-Lewis, V., Jordan-Sciutto, K. L., Hayley, S., Mount, M. P., et al. (2003). Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proceedings of the National Academy of Sciences USA, 100(23), 13650–13655.CrossRef
Su, S. C., & Tsai, L. H. (2011). Cyclin-dependent kinases in brain development and disease. Annual Review of Cell and Developmental Biology, 27, 465–491.CrossRefPubMed
Sun, K. H., Chang, K. H., Clawson, S., Ghosh, S., Mirzaei, H., Regnier, F., et al. (2011). Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity. Journal of Neurochemistry, 118(5), 902–914.CrossRefPubMed
Tan, T. C., Valova, V. A., Malladi, C. S., Graham, M. E., Berven, L. A., Jupp, O. J., et al. (2003). Cdk5 is essential for synaptic vesicle endocytosis. Nature Cell Biology, 5(8), 701–710.CrossRefPubMed
Tang, D., Chun, A. C., Zhang, M., & Wang, J. H. (1997). Cyclin-dependent kinase 5 (Cdk5) activation domain of neuronal Cdk5 activator. Evidence of the existence of cyclin fold in neuronal Cdk5a activator. Journal of Biological Chemistry, 272(19), 12318–12327.CrossRefPubMed
Tang, D., Yeung, J., Lee, K. Y., Matsushita, M., Matsui, H., Tomizawa, K., et al. (1995). An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. Journal of Biological Chemistry, 270(45), 26897–26903.CrossRefPubMed
Tarricone, C., Dhavan, R., Peng, J., Areces, L. B., Tsai, L. H., & Musacchio, A. (2001). Structure and regulation of the CDK5-p25(nck5a) complex. Molecular Cell, 8(3), 657–669.CrossRefPubMed
Tatham, M. H., Jaffray, E., Vaughan, O. A., Desterro, J. M., Botting, C. H., Naismith, J. H., et al. (2001). Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. Journal of Biological Chemistry, 276(38), 35368–35374.CrossRefPubMed
Tsai, L. H., Delalle, I., Caviness, V. S, Jr, Chae, T., & Harlow, E. (1994). p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature, 371(6496), 419–423.CrossRefPubMed
van den Heuvel, S., & Harlow, E. (1993). Distinct roles for cyclin-dependent kinases in cell cycle control. Science, 262(5142), 2050–2054.CrossRefPubMed
Verstegen, A. M., Tagliatti, E., Lignani, G., Marte, A., Stolero, T., Atias, M., et al. (2014). Phosphorylation of synapsin I by cyclin-dependent kinase-5 sets the ratio between the resting and recycling pools of synaptic vesicles at hippocampal synapses. Journal of Neuroscience, 34(21), 7266–7280.CrossRefPubMed
Weishaupt, J. H., Kussmaul, L., Grotsch, P., Heckel, A., Rohde, G., Romig, H., et al. (2003). Inhibition of CDK5 is protective in necrotic and apoptotic paradigms of neuronal cell death and prevents mitochondrial dysfunction. Molecular and Cellular Neuroscience, 24(2), 489–502.CrossRefPubMed
Wittmann, C., Chockley, P., Singh, S. K., Pase, L., Lieschke, G. J., & Grabher, C. (2012). Hydrogen peroxide in inflammation: messenger, guide, and assassin. Advances in Hematology, 2012, 541471.CrossRefPubMedCentralPubMed
Zukerberg, L. R., Patrick, G. N., Nikolic, M., Humbert, S., Wu, C. L., Lanier, L. M., et al. (2000). Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron, 26(3), 633–646.CrossRefPubMed
Metadaten
Titel
Sumoylation of p35 Modulates p35/Cyclin-Dependent Kinase (Cdk) 5 Complex Activity
verfasst von
Anja Büchner
Petranka Krumova
Sundar Ganesan
Mathias Bähr
Katrin Eckermann
Jochen H. Weishaupt
Publikationsdatum
01.03.2015
Verlag
Springer US
Erschienen in
NeuroMolecular Medicine / Ausgabe 1/2015
Print ISSN: 1535-1084
Elektronische ISSN: 1559-1174
DOI
https://doi.org/10.1007/s12017-014-8336-4

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