UniProt functional annotation for Q63450



	UniProt functional annotation for Q63450

UniProt code: Q63450.

Organism: Rattus norvegicus (Rat).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.

Function: Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, regulates transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization and neurite outgrowth. Recognizes the substrate consensus sequence [MVLIF]-x-R-x(2)-[ST]-x(3)-[MVLIF]. Regulates axonal extension and growth cone motility in hippocampal and cerebellar nerve cells. Upon NMDA receptor-mediated Ca(2+) elevation, promotes dendritic growth in hippocampal neurons and is essential in synapses for full long-term potentiation (LTP) and ERK2-dependent translational activation. Downstream of NMDA receptors, promotes the formation of spines and synapses in hippocampal neurons by phosphorylating ARHGEF7/BETAPIX on 'Ser-516', which results in the enhancement of ARHGEF7 activity and activation of RAC1. Promotes neuronal differentiation and neurite outgrowth by activation and phosphorylation of MARK2 on 'Ser-91', 'Ser- 92', 'Ser-93' and 'Ser-294'. Promotes nuclear export of HDAC5 and binding to 14-3-3 by phosphorylation of 'Ser-259' and 'Ser-498' in the regulation of muscle cell differentiation (By similarity). Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-275' and 'Ser-294'. Involved in the regulation of basal and estrogen-stimulated migration of medulloblastoma cells through ARHGEF7/BETAPIX phosphorylation (By similarity). Is required for proper activation of cyclin-D1/CDK4 complex during G1 progression in diploid fibroblasts. Plays a role in K(+) and ANG2-mediated regulation of the aldosterone synthase (CYP11B2) to produce aldosterone in the adrenal cortex. Phosphorylates EIF4G3/eIF4GII. In vitro phosphorylates CREB1, ATF1, CFTR, MYL9 and SYN1/synapsin I. {ECO:0000250, ECO:0000269|PubMed:12081505, ECO:0000269|PubMed:15084659, ECO:0000269|PubMed:15689566, ECO:0000269|PubMed:1646483, ECO:0000269|PubMed:16772171, ECO:0000269|PubMed:17022975, ECO:0000269|PubMed:21107644, ECO:0000269|PubMed:8621702}.

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.17; Evidence={ECO:0000269|PubMed:8631893, ECO:0000269|PubMed:8702851};

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.17; Evidence={ECO:0000269|PubMed:8631893, ECO:0000269|PubMed:8702851};

Activity regulation: Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows phosphorylation of Thr-177 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-177 results in several fold increase in total activity. Unlike CaMK4, is unable to exhibit autonomous activity after Ca(2+)/calmodulin activation. {ECO:0000269|PubMed:8631893, ECO:0000269|PubMed:8702851}.

Subunit: Monomer. Interacts with XPO1. {ECO:0000269|PubMed:12475216, ECO:0000269|PubMed:15147908}.

Subcellular location: Cytoplasm. Nucleus. Note=Predominantly cytoplasmic.

Tissue specificity: Widely expressed. {ECO:0000269|PubMed:7624832}.

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:12475216}.

Ptm: Phosphorylated by CaMKK1 and CaMKK2 on Thr-177. {ECO:0000269|PubMed:8631893}.

Ptm: Polybiquitinated by the E3 ubiquitin-protein ligase complex SCF(FBXL12), leading to proteasomal degradation. {ECO:0000250}.

Miscellaneous: Dendrite development is blocked in hippocampal neurons silencing CAKM1.

Similarity: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily. {ECO:0000305}.

Sequence caution: Sequence=AAA19670.1; Type=Frameshift; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Rattus norvegicus (Rat).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.



Function:		Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, regulates transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization and neurite outgrowth. Recognizes the substrate consensus sequence [MVLIF]-x-R-x(2)-[ST]-x(3)-[MVLIF]. Regulates axonal extension and growth cone motility in hippocampal and cerebellar nerve cells. Upon NMDA receptor-mediated Ca(2+) elevation, promotes dendritic growth in hippocampal neurons and is essential in synapses for full long-term potentiation (LTP) and ERK2-dependent translational activation. Downstream of NMDA receptors, promotes the formation of spines and synapses in hippocampal neurons by phosphorylating ARHGEF7/BETAPIX on 'Ser-516', which results in the enhancement of ARHGEF7 activity and activation of RAC1. Promotes neuronal differentiation and neurite outgrowth by activation and phosphorylation of MARK2 on 'Ser-91', 'Ser- 92', 'Ser-93' and 'Ser-294'. Promotes nuclear export of HDAC5 and binding to 14-3-3 by phosphorylation of 'Ser-259' and 'Ser-498' in the regulation of muscle cell differentiation (By similarity). Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-275' and 'Ser-294'. Involved in the regulation of basal and estrogen-stimulated migration of medulloblastoma cells through ARHGEF7/BETAPIX phosphorylation (By similarity). Is required for proper activation of cyclin-D1/CDK4 complex during G1 progression in diploid fibroblasts. Plays a role in K(+) and ANG2-mediated regulation of the aldosterone synthase (CYP11B2) to produce aldosterone in the adrenal cortex. Phosphorylates EIF4G3/eIF4GII. In vitro phosphorylates CREB1, ATF1, CFTR, MYL9 and SYN1/synapsin I. {ECO:0000250, ECO:0000269\|PubMed:12081505, ECO:0000269\|PubMed:15084659, ECO:0000269\|PubMed:15689566, ECO:0000269\|PubMed:1646483, ECO:0000269\|PubMed:16772171, ECO:0000269\|PubMed:17022975, ECO:0000269\|PubMed:21107644, ECO:0000269\|PubMed:8621702}.


Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.17; Evidence={ECO:0000269\|PubMed:8631893, ECO:0000269\|PubMed:8702851};
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.17; Evidence={ECO:0000269\|PubMed:8631893, ECO:0000269\|PubMed:8702851};
Activity regulation:		Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows phosphorylation of Thr-177 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-177 results in several fold increase in total activity. Unlike CaMK4, is unable to exhibit autonomous activity after Ca(2+)/calmodulin activation. {ECO:0000269\|PubMed:8631893, ECO:0000269\|PubMed:8702851}.
Subunit:		Monomer. Interacts with XPO1. {ECO:0000269\|PubMed:12475216, ECO:0000269\|PubMed:15147908}.
Subcellular location:		Cytoplasm. Nucleus. Note=Predominantly cytoplasmic.
Tissue specificity:		Widely expressed. {ECO:0000269\|PubMed:7624832}.
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:12475216}.
Ptm:		Phosphorylated by CaMKK1 and CaMKK2 on Thr-177. {ECO:0000269\|PubMed:8631893}.
Ptm:		Polybiquitinated by the E3 ubiquitin-protein ligase complex SCF(FBXL12), leading to proteasomal degradation. {ECO:0000250}.
Miscellaneous:		Dendrite development is blocked in hippocampal neurons silencing CAKM1.
Similarity:		Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily. {ECO:0000305}.
Sequence caution:		Sequence=AAA19670.1; Type=Frameshift; Evidence={ECO:0000305};