Abstract
CASK, a scaffolding protein present in neuronal synapses and other cell junctions, contains a CaM-kinase domain at its N terminus. Due to lack of adequate biochemical data and based on bioinformatics, this domain was classified as a pseudokinase. But new evidence suggests that CASK is a unique kinase which is independent of divalent cofactors. Surprisingly, it is inhibited by many divalent ions which include the essential kinase cofactor magnesium. The inability of CASK to use a cofactor makes it a very slow enzyme; however, this disadvantage of CASK is partially compensated by substrate docking to its scaffolding domains. Indeed, the only characterized substrate to date is Neurexin, which is recruited to CASK via its PDZ domain. Synaptic activity inhibits Neurexin phosphorylation by CASK due to acute influx of divalent ions indicating the divalent ion sensitivity might be a regulatory mechanism. The biological role of this kinase activity remains unclear. It is quite possible that similar to CASK other classified pseudokinases might also turn out to be specialized kinases working in particular physiological niche. Since the discovery of CASK as an active kinase, at least another pseudokinase has turned out to be an active enzyme.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Hata Y, Butz S, Sudhof TC (1996) CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J Neurosci 16:2488–2494
te Velthuis AJ, Admiraal JF, Bagowski CP (2007) Molecular evolution of the MAGUK family in metazoan genomes. BMC Evol Biol 7:129
Hsueh YP (2006) The role of the MAGUK protein CASK in neural development and synaptic function. Curr Med Chem 13: 1915–1927
Cuthbert PC, Stanford LE, Coba MP, Ainge JA, Fink AE, Opazo P, Delgado JY, Komiyama NH, O’Dell TJ, Grant SG (2007) Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies. J Neurosci 27: 2673–2682
Mendoza-Topaz C, Urra F, Barria R, Albornoz V, Ugalde D, Thomas U, Gundelfinger ED, Delgado R, Kukuljan M, Sanxaridis PD, Tsunoda S, Ceriani MF, Budnik V, Sierralta J (2008) DLGS97/SAP97 is developmentally upregulated and is required for complex adult behaviors and synapse morphology and function. J Neurosci 28:304–314
Najm J, Horn D, Wimplinger I, Golden JA, Chizhikov VV, Sudi J, Christian SL, Ullmann R, Kuechler A, Haas CA, Flubacher A, Charnas LR, Uyanik G, Frank U, Klopocki E, Dobyns WB, Kutsche K (2008) Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet 40(90):1065–1067
Froyen G, Van Esch H, Bauters M, Hollanders K, Frints SG, Vermeesch JR, Devriendt K, Fryns JP, Marynen P (2007) Detection of genomic copy number changes in patients with idiopathic mental retardation by high-resolution X-array-CGH: important role for increased gene dosage of XLMR genes. Hum Mutat 28:1034–1042
Piluso G, D’Amico F, Saccone V, Bismuto E, Rotundo IL, Di Domenico M, Aurino S, Schwartz CE, Neri G, Nigro V (2009) A missense mutation in CASK causes FG syndrome in an Italian family. Am J Hum Genet 84:162–177
Atasoy D, Schoch S, Ho A, Nadasy KA, Liu X, Zhang W, Mukherjee K, Nosyreva ED, Fernandez-Chacon R, Missler M, Kavalali ET, Sudhof TC (2007) Deletion of CASK in mice is lethal and impairs synaptic function. Proc Natl Acad Sci USA 104:2525–2530
Butz S, Okamoto M, Sudhof TC (1998) A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Cell 94:773–782
Kaech SM, Whitfield CW, Kim SK (1998) The LIN-2/LIN-7/LIN-10 complex mediates basolateral membrane localization of the C. elegans EGF receptor LET-23 in vulval epithelial cells. Cell 94:761–771
Hsueh YP, Wang TF, Yang FC, Sheng M (2000) Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature 404: 298–302
Qi J, Su Y, Sun R, Zhang F, Luo X, Yang Z (2005) CASK inhibits ECV304 cell growth and interacts with Id1. Biochem Biophys Res Commun 328:517–521
Sanford JL, Mays TA, Rafael-Fortney JA (2004) CASK and Dlg form a PDZ protein complex at the mammalian neuromuscular junction. Muscle Nerve 30:164–171
Samuels BA, Hsueh YP, Shu T, Liang H, Tseng HC, Hong CJ, Su SC, Volker J, Neve RL, Yue DT, Tsai LH (2007) Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK. Neuron 56:823–837
Tabuchi K, Biederer T, Butz S, Sudhof TC (2002) CASK participates in alternative tripartite complexes in which Mint 1 competes for binding with caskin 1, a novel CASK-binding protein. J Neurosci 22:4264–4273
Maximov A, Sudhof TC, Bezprozvanny I (1999) Association of neuronal calcium channels with modular adaptor proteins. J Biol Chem 274:24453–24456
Maximov A, Bezprozvanny I (2002) Synaptic targeting of N-type calcium channels in hippocampal neurons. J Neurosci 22:6939–6952
Hoskins R, Hajnal AF, Harp SA, Kim SK (1996) The C. elegans vulval induction gene lin-2 encodes a member of the MAGUK family of cell junction proteins. Development 122:97–111
Lu CS, Hodge JJ, Mehren J, Sun XX, Griffith LC (2003) Regulation of the Ca2+/CaM-responsive pool of CaMKII by scaffold-dependent autophosphorylation. Neuron 40:1185–1197
Hodge JJ, Mullasseril P, Griffith LC (2006) Activity-dependent gating of CaMKII autonomous activity by Drosophila CASK. Neuron 51:327–337
Marble DD, Hegle AP, Snyder ED II, Dimitratos S, Bryant PJ, Wilson GF (2005) Camguk/CASK enhances Ether-a-go-go potassium current by a phosphorylation-dependent mechanism. J Neurosci 25:4898–4907
Martin JR, Ollo R (1996) A new Drosophila Ca2+/calmodulin-dependent protein kinase (Caki) is localized in the central nervous system and implicated in walking speed. EMBO J 15:1865–1876
Chao HW, Hong CJ, Huang TN, Lin YL, Hsueh YP (2008) SUMOylation of the MAGUK protein CASK regulates dendritic spinogenesis. J Cell Biol 182:141–155
Sun Q, Kelly GM (2010) Post-translational modification of CASK leads to its proteasome-dependent degradation. Int J Biochem Cell Biol 42:90–97
Mukherjee K, Sharma M, Urlaub H, Bourenkov GP, Jahn R, Sudhof TC, Wahl MC (2008) CASK Functions as a Mg2+-independent neurexin kinase. Cell 133:328–339
Goldberg J, Nairn AC, Kuriyan J (1996) Structural basis for the autoinhibition of calcium/calmodulin-dependent protein kinase I. Cell 84:875–887
Mukherjee K, Sharma M, Jahn R, Wahl MC, Sudhof TC (2010) Evolution of CASK into a Mg2+-sensitive kinase. Sci Signal 3:ra33
Dimitratos SD, Woods DF, Bryant PJ (1997) Camguk, Lin-2, and CASK: novel membrane-associated guanylate kinase homologs that also contain CaM-kinase domains. Mech Dev 63:127–130
Tereshko V, Teplova M, Brunzelle J, Watterson DM, Egli M (2001) Crystal structures of the catalytic domain of human protein kinase associated with apoptosis and tumor suppression. Nat Struct Biol 8:899–907
Colbran RJ, Smith MK, Schworer CM, Fong YL, Soderling TR (1989) Regulatory domain of calcium/calmodulin-dependent protein kinase II. Mechanism of inhibition and regulation by phosphorylation. J Biol Chem 264:4800–4804
Rosenberg OS, Deindl S, Sung RJ, Nairn AC, Kuriyan J (2005) Structure of the autoinhibited kinase domain of CaMKII and SAXS analysis of the holoenzyme. Cell 123: 849–860
Fong YL, Soderling TR (1990) Studies on the regulatory domain of Ca2+/calmodulin-dependent protein kinase II. Functional analyses of arginine 283 using synthetic inhibitory peptides and site-directed mutagenesis of the alpha subunit. J Biol Chem 265:11091–11097
Daniels DL, Cohen AR, Anderson JM, Brunger AT (1998) Crystal structure of the hCASK PDZ domain reveals the structural basis of class II PDZ domain target recognition. Nat Struct Biol 5:317–325
Li Y, Spangenberg O, Paarmann I, Konrad M, Lavie A (2002) Structural basis for nucleotide-dependent regulation of membrane-associated guanylate kinase-like domains. J Biol Chem 277:4159–4165
Adams JA (2001) Kinetic and catalytic mechanisms of protein kinases. Chem Rev 101: 2271–2290
Waas WF, Rainey MA, Szafranska AE, Cox K, Dalby KN (2004) A kinetic approach towards understanding substrate interactions and the catalytic mechanism of the serine/threonine protein kinase ERK2: identifying a potential regulatory role for divalent magnesium. Biochim Biophys Acta 1697:81–87
Schnell S, Turner TE (2004) Reaction kinetics in intracellular environments with macromolecular crowding: simulations and rate laws. Prog Biophys Mol Biol 85:235–260
Huse M, Kuriyan J (2002) The conformational plasticity of protein kinases. Cell 109:275–282
Dimitratos SD, Woods DF, Stathakis DG, Bryant PJ (1999) Signaling pathways are focused at specialized regions of the plasma membrane by scaffolding proteins of the MAGUK family. Bioessays 21:912–921
Olsen O, Bredt DS (2003) Functional analysis of the nucleotide binding domain of membrane-associated guanylate kinases. J Biol Chem 278:6873–6878
Borg JP, Straight SW, Kaech SM, de Taddeo-Borg M, Kroon DE, Karnak D, Turner RS, Kim SK, Margolis B (1998) Identification of an evolutionarily conserved heterotrimeric protein complex involved in protein targeting. J Biol Chem 273:31633–31636
Lozovatsky L, Abayasekara N, Piawah S, Walther Z (2009) CASK deletion in intestinal epithelia causes mislocalization of LIN7C and the DLG1/Scrib polarity complex without affecting cell polarity. Mol Biol Cell 20:4489–4499
Slawson JB, Kuklin EA, Ejima A, Mukherjee K, Ostrovsky L, Griffith LC (2011) Central regulation of locomotor behavior of Drosophila melanogaster depends on a CASK isoform containing CaMK-like and L27 domains. Genetics 187:171–184
Sun M, Liu L, Zeng X, Xu M, Fang M, Xie W (2009) Genetic interaction between Neurexin and CAKI/CMG is important for synaptic function in Drosophila neuromuscular junction. Neurosci Res 64:362–371
de Mendoza A, Suga H, Ruiz-Trillo I (2010) Evolution of the MAGUK protein gene family in premetazoan lineages. BMC Evol Biol 10:93
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Mukherjee, K. (2012). CASK: A Specialized Neuronal Kinase. In: Mukai, H. (eds) Protein Kinase Technologies. Neuromethods, vol 68. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-824-5_5
Download citation
DOI: https://doi.org/10.1007/978-1-61779-824-5_5
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-61779-823-8
Online ISBN: 978-1-61779-824-5
eBook Packages: Springer Protocols