2w4o

Structural highlights

Function

[KCC4_HUMAN] Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK4 signaling cascade and regulates, mainly by phosphorylation, the activity of several transcription activators, such as CREB1, MEF2D, JUN and RORA, which play pivotal roles in immune response, inflammation, and memory consolidation. In the thymus, regulates the CD4(+)/CD8(+) double positive thymocytes selection threshold during T-cell ontogeny. In CD4 memory T-cells, is required to link T-cell antigen receptor (TCR) signaling to the production of IL2, IFNG and IL4 (through the regulation of CREB and MEF2). Regulates the differentiation and survival phases of osteoclasts and dendritic cells (DCs). Mediates DCs survival by linking TLR4 and the regulation of temporal expression of BCL2. Phosphorylates the transcription activator CREB1 on 'Ser-133' in hippocampal neuron nuclei and contribute to memory consolidation and long term potentiation (LTP) in the hippocampus. Can activate the MAP kinases MAPK1/ERK2, MAPK8/JNK1 and MAPK14/p38 and stimulate transcription through the phosphorylation of ELK1 and ATF2. Can also phosphorylate in vitro CREBBP, PRM2, MEF2A and STMN1/OP18.^{[1] [2] [3] [4] [5] [6] [7] [8]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Tokumitsu H, Brickey DA, Glod J, Hidaka H, Sikela J, Soderling TR. Activation mechanisms for Ca2+/calmodulin-dependent protein kinase IV. Identification of a brain CaM-kinase IV kinase. J Biol Chem. 1994 Nov 18;269(46):28640-7. PMID:7961813
2. ↑ Matthews RP, Guthrie CR, Wailes LM, Zhao X, Means AR, McKnight GS. Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression. Mol Cell Biol. 1994 Sep;14(9):6107-16. PMID:8065343
3. ↑ Bito H, Deisseroth K, Tsien RW. CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression. Cell. 1996 Dec 27;87(7):1203-14. PMID:8980227
4. ↑ Enslen H, Tokumitsu H, Stork PJ, Davis RJ, Soderling TR. Regulation of mitogen-activated protein kinases by a calcium/calmodulin-dependent protein kinase cascade. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10803-8. PMID:8855261
5. ↑ Melander Gradin H, Marklund U, Larsson N, Chatila TA, Gullberg M. Regulation of microtubule dynamics by Ca2+/calmodulin-dependent kinase IV/Gr-dependent phosphorylation of oncoprotein 18. Mol Cell Biol. 1997 Jun;17(6):3459-67. PMID:9154845
6. ↑ Blaeser F, Ho N, Prywes R, Chatila TA. Ca(2+)-dependent gene expression mediated by MEF2 transcription factors. J Biol Chem. 2000 Jan 7;275(1):197-209. PMID:10617605
7. ↑ Illario M, Giardino-Torchia ML, Sankar U, Ribar TJ, Galgani M, Vitiello L, Masci AM, Bertani FR, Ciaglia E, Astone D, Maulucci G, Cavallo A, Vitale M, Cimini V, Pastore L, Means AR, Rossi G, Racioppi L. Calmodulin-dependent kinase IV links Toll-like receptor 4 signaling with survival pathway of activated dendritic cells. Blood. 2008 Jan 15;111(2):723-31. Epub 2007 Oct 1. PMID:17909078 doi:http://dx.doi.org/10.1182/blood-2007-05-091173
8. ↑ Fukushima H, Maeda R, Suzuki R, Suzuki A, Nomoto M, Toyoda H, Wu LJ, Xu H, Zhao MG, Ueda K, Kitamoto A, Mamiya N, Yoshida T, Homma S, Masushige S, Zhuo M, Kida S. Upregulation of calcium/calmodulin-dependent protein kinase IV improves memory formation and rescues memory loss with aging. J Neurosci. 2008 Oct 1;28(40):9910-9. doi: 10.1523/JNEUROSCI.2625-08.2008. PMID:18829949 doi:http://dx.doi.org/10.1523/JNEUROSCI.2625-08.2008