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MGP000401

UniProt Annotations

Entry Information

Gene Name	calcium/calmodulin-dependent protein kinase IV
Protein Entry
UniProt ID	Q16566
Species	Human

Comments

Comment type	Description
Catalytic Activity	ATP + a protein = ADP + a phosphoprotein.
Developmental Stage	Expressed during differentiation of monocyte- derived dendritic cells (at protein level). {ECO:0000269\|PubMed:17909078}.
Domain	The autoinhibitory domain overlaps with the calmodulin binding region and interacts in the inactive folded state with the catalytic domain as a pseudosubstrate. {ECO:0000269\|PubMed:7961813}.
Enzyme Regulation	Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows phosphorylation of Thr-200 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-200 results in a 10-20-fold increase in total activity to generate Ca(2+)/calmodulin-independent activity. Autophosphorylation of the N-terminus Ser-12 and Ser-13 is required for full activation. Inactivated by protein phosphatase 2A (PPP2CA/PPP2CB) which dephosphorylates Thr-200, thereby terminating autonomous activity and helping to maintain the enzyme in its autoinhibited state. {ECO:0000269\|PubMed:15143065, ECO:0000269\|PubMed:15769749, ECO:0000269\|PubMed:8702940}.
Function	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. {ECO:0000269\|PubMed:10617605, ECO:0000269\|PubMed:17909078, ECO:0000269\|PubMed:18829949, ECO:0000269\|PubMed:7961813, ECO:0000269\|PubMed:8065343, ECO:0000269\|PubMed:8855261, ECO:0000269\|PubMed:8980227, ECO:0000269\|PubMed:9154845}.
Ptm	Glycosylation at Ser-189 modulates the phosphorylation of CaMK4 at Thr-200 and negatively regulates its activity toward CREB1 in basal conditions and during early inomycin stimulation. {ECO:0000269\|PubMed:15143065, ECO:0000269\|PubMed:19506079, ECO:0000269\|PubMed:8702940}.
Ptm	Phosphorylated by CaMKK1 and CaMKK2 on Thr-200. Dephosphorylated by protein phosphatase 2A. Autophosphorylated on Ser-12 and Ser-13. {ECO:0000269\|PubMed:15143065, ECO:0000269\|PubMed:19506079, ECO:0000269\|PubMed:19690332, ECO:0000269\|PubMed:8702940}.
Sequence Caution	Sequence=AAH16695.2; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305};
Similarity	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily. {ECO:0000305}.
Similarity	Contains 1 protein kinase domain. {ECO:0000255\|PROSITE-ProRule:PRU00159}.
Subcellular Location	Cytoplasm. Nucleus. Note=Localized in hippocampal neuron nuclei. In spermatids, associated with chromatin and nuclear matrix (By similarity). {ECO:0000250}.
Subunit	Monomer (By similarity). Interacts with protein phosphatase 2A (PPP2CA/PPP2CB); the interaction is mutually exclusive with binding to Ca(2+)/calmodulin. {ECO:0000250, ECO:0000269\|PubMed:15143065, ECO:0000269\|Ref.26}.
Tissue Specificity	Expressed in brain, thymus, CD4 T-cells, testis and epithelial ovarian cancer tissue. {ECO:0000269\|PubMed:12065094, ECO:0000269\|PubMed:7961813, ECO:0000269\|PubMed:8397199}.