KKCC2_RAT
ID KKCC2_RAT Reviewed; 587 AA.
AC O88831;
DT 07-DEC-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 1.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Calcium/calmodulin-dependent protein kinase kinase 2;
DE Short=CaM-KK 2;
DE Short=CaM-kinase kinase 2;
DE Short=CaMKK 2;
DE EC=2.7.11.17;
DE AltName: Full=Calcium/calmodulin-dependent protein kinase kinase beta;
DE Short=CaM-KK beta;
DE Short=CaM-kinase kinase beta;
DE Short=CaMKK beta;
GN Name=Camkk2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Cerebellum;
RX PubMed=9276695; DOI=10.1093/oxfordjournals.jbchem.a021735;
RA Kitani T., Okuno S., Fujisawa H.;
RT "Molecular cloning of Ca2+/calmodulin-dependent protein kinase kinase
RT beta.";
RL J. Biochem. 122:243-250(1997).
RN [2]
RP PROTEIN SEQUENCE OF 180-184; 227-280; 290-294; 298-306; 327-335; 338-355;
RP 403-418; 425-429; 434-445; 448-469 AND 494-503, AND FUNCTION IN
RP PHOSPHORYLATION OF CAMK1 AND CAMK4.
RX PubMed=8631893; DOI=10.1074/jbc.271.18.10806;
RA Edelman A.M., Mitchelhill K.I., Selbert M.A., Anderson K.A., Hook S.S.,
RA Stapleton D., Goldstein E.G., Means A.R., Kemp B.E.;
RT "Multiple Ca(2+)-calmodulin-dependent protein kinase kinases from rat
RT brain. Purification, regulation by Ca(2+)-calmodulin, and partial amino
RT acid sequence.";
RL J. Biol. Chem. 271:10806-10810(1996).
RN [3]
RP CHARACTERIZATION, INTERACTION WITH CALMODULIN, FUNCTION IN PHOSPHORYLATION
RP OF CAMK1 AND CAMK4, AND AUTOPHOSPHORYLATION.
RX PubMed=9822657; DOI=10.1074/jbc.273.48.31880;
RA Anderson K.A., Means R.L., Huang Q.-H., Kemp B.E., Goldstein E.G.,
RA Selbert M.A., Edelman A.M., Fremeau R.T., Means A.R.;
RT "Components of a calmodulin-dependent protein kinase cascade. Molecular
RT cloning, functional characterization and cellular localization of
RT Ca2+/calmodulin-dependent protein kinase kinase beta.";
RL J. Biol. Chem. 273:31880-31889(1998).
RN [4]
RP SUBCELLULAR LOCATION.
RX PubMed=10651863; DOI=10.1046/j.1460-9568.2000.00883.x;
RA Sakagami H., Umemiya M., Saito S., Kondo H.;
RT "Distinct immunohistochemical localization of two isoforms of
RT Ca2+/calmodulin-dependent protein kinase kinases in the adult rat brain.";
RL Eur. J. Neurosci. 12:89-99(2000).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=11264466; DOI=10.1146/annurev.pharmtox.41.1.471;
RA Hook S.S., Means A.R.;
RT "Ca(2+)/CaM-dependent kinases: from activation to function.";
RL Annu. Rev. Pharmacol. Toxicol. 41:471-505(2001).
RN [6]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=21807092; DOI=10.1016/j.cellsig.2011.07.014;
RA Green M.F., Anderson K.A., Means A.R.;
RT "Characterization of the CaMKKbeta-AMPK signaling complex.";
RL Cell. Signal. 23:2005-2012(2011).
RN [7]
RP FUNCTION, TISSUE SPECIFICITY, AND IDENTIFICATION OF ISOFORM 2.
RX PubMed=21957496; DOI=10.4161/rna.8.6.16691;
RA Cao W., Sohail M., Liu G., Koumbadinga G.A., Lobo V.G., Xie J.;
RT "Differential effects of PKA-controlled CaMKK2 variants on neuronal
RT differentiation.";
RL RNA Biol. 8:1061-1072(2011).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-494 AND SER-510, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Calcium/calmodulin-dependent protein kinase belonging to a
CC proposed calcium-triggered signaling cascade involved in a number of
CC cellular processes. Phosphorylates CAMK1 and CAMK4. Phosphorylates
CC CAMK1D (By similarity). Seems to be involved in hippocampal activation
CC of CREB1 (By similarity). Efficiently phosphorylates 5'-AMP-activated
CC protein kinase (AMPK) trimer, including that consisting of PRKAA1,
CC PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to
CC Ca(2+) signals. May play a role in neurite growth. Isoform 2 may
CC promote neurite elongation, while isoform 1 may promoter neurite
CC branching. {ECO:0000250, ECO:0000269|PubMed:21807092,
CC ECO:0000269|PubMed:21957496, ECO:0000269|PubMed:8631893,
CC ECO:0000269|PubMed:9822657}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.17;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.17;
CC -!- ACTIVITY REGULATION: Activated by Ca(2+)/calmodulin. Binding of
CC calmodulin may relieve intrasteric autoinhibition. Autophosphorylation
CC does not alter activity or regulation by Ca(2+)/calmodulin. In part,
CC activity is independent on Ca(2+)/calmodulin.
CC -!- SUBUNIT: Interacts with calmodulin. {ECO:0000269|PubMed:9822657}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q96RR4}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q96RR4}. Cell projection, neuron projection
CC {ECO:0000250|UniProtKB:Q96RR4}. Note=Predominantly nuclear in
CC unstimulated cells, relocalizes into cytoplasm and neurites after
CC forskolin induction. {ECO:0000250|UniProtKB:Q96RR4}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=CAMKK2+E16;
CC IsoId=O88831-1; Sequence=Displayed;
CC Name=2; Synonyms=CAMKK2-E16;
CC IsoId=O88831-2; Sequence=VSP_046047;
CC -!- TISSUE SPECIFICITY: Mainly expressed in brain, but detected in all
CC tissues tested (at protein level). In the brain, isoform 1 may be
CC predominant. with high levels in the cerebellum and hippocampus,
CC although isoform 3 is detectable. Isoform 3 is also expressed in lung.
CC {ECO:0000269|PubMed:21957496}.
CC -!- DOMAIN: The autoinhibitory domain overlaps with the calmodulin binding
CC region and may be involved in intrasteric autoinhibition.
CC -!- DOMAIN: The RP domain (arginine/proline-rich) is involved in the
CC recognition of CAMKI and CAMK4 as substrates. {ECO:0000250}.
CC -!- PTM: Phosphorylated by PKA (By similarity). Each isoform may show a
CC different pattern of phosphorylation (By similarity).
CC Autophosphorylated. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; AB018081; BAA33524.1; -; mRNA.
DR PIR; JC5669; JC5669.
DR RefSeq; NP_112628.1; NM_031338.1. [O88831-1]
DR AlphaFoldDB; O88831; -.
DR SMR; O88831; -.
DR BioGRID; 249725; 7.
DR STRING; 10116.ENSRNOP00000001774; -.
DR ChEMBL; CHEMBL1795115; -.
DR iPTMnet; O88831; -.
DR PhosphoSitePlus; O88831; -.
DR SwissPalm; O88831; -.
DR PaxDb; O88831; -.
DR PRIDE; O88831; -.
DR GeneID; 83506; -.
DR KEGG; rno:83506; -.
DR UCSC; RGD:620092; rat. [O88831-1]
DR CTD; 10645; -.
DR RGD; 620092; Camkk2.
DR eggNOG; KOG0585; Eukaryota.
DR InParanoid; O88831; -.
DR OrthoDB; 856506at2759; -.
DR PhylomeDB; O88831; -.
DR Reactome; R-RNO-111932; CaMK IV-mediated phosphorylation of CREB.
DR Reactome; R-RNO-442729; CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde.
DR Reactome; R-RNO-9619229; Activation of RAC1 downstream of NMDARs.
DR PRO; PR:O88831; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0043005; C:neuron projection; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0005516; F:calmodulin binding; IDA:RGD.
DR GO; GO:0004683; F:calmodulin-dependent protein kinase activity; IDA:RGD.
DR GO; GO:0030295; F:protein kinase activator activity; TAS:RGD.
DR GO; GO:0004672; F:protein kinase activity; TAS:RGD.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0032147; P:activation of protein kinase activity; IDA:RGD.
DR GO; GO:0061762; P:CAMKK-AMPK signaling cascade; ISO:RGD.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; ATP-binding; Calmodulin-binding;
KW Cell projection; Cytoplasm; Direct protein sequencing; Kinase;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q96RR4"
FT CHAIN 2..587
FT /note="Calcium/calmodulin-dependent protein kinase kinase
FT 2"
FT /id="PRO_0000086146"
FT DOMAIN 164..445
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..32
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 74..115
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 203..225
FT /note="RP domain"
FT REGION 204..224
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 471..476
FT /note="Autoinhibitory domain"
FT /evidence="ECO:0000250"
FT REGION 474..499
FT /note="Calmodulin-binding"
FT /evidence="ECO:0000250"
FT REGION 496..587
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..15
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 92..115
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 522..538
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 569..587
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 311
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 170..178
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 193
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:Q96RR4"
FT MOD_RES 99
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8C078"
FT MOD_RES 113
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96RR4"
FT MOD_RES 128
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96RR4"
FT MOD_RES 132
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8C078"
FT MOD_RES 136
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8C078"
FT MOD_RES 494
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 510
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 571
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8C078"
FT VAR_SEQ 519..587
FT /note="KPTREWEPLSEPKEARQRRQPPGPRASPCGGGGSALVKGGPCVESCGAPAPG
FT SPPRTPPQQPEEAMEPE -> QGSEDSLRGPEPAPVGEEEVLL (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_046047"
FT CONFLICT 180
FT /note="L -> S (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 245
FT /note="P -> V (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 300
FT /note="Missing (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 465
FT /note="V -> S (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 468
FT /note="E -> T (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 587 AA; 64446 MW; C9E49B72578F3971 CRC64;
MSSCVSSQPT SDRAAPQDEL GSGGVSRESQ KPCEALRGLS SLSIHLGMES FIVVTECEPG
RGVDLSLARD QPLEADGQEL PLDASEPESR SLLSGGKMSL QERSQGGPAS SSSLDMNGRC
ICPSLSYSPA SSPQSSPRMP RRPTVESHHV SITGLQDCVQ LNQYTLKDEI GKGSYGVVKL
AYNENDNTYY AMKVLSKKKL IRQAGFPRRP PPRGTRPAPG GCIQPRGPIE QVYQEIAILK
KLDHPNVVKL VEVLDDPNED HLYMVFELVN QGPVMEVPTL KPLSEDQARF YFQDLIKGIE
YLHYQKIIHR DIKPSNLLVG EDGHIKIADF GVSNEFKGSD ALLSNTVGTP AFMAPESLSE
TRKIFSGKAL DVWAMGVTLY CFVFGQCPFM DERIMCLHSK IKSQALEFPD QPDIAEDLKD
LITRMLDKNP ESRIVVPEIK LHPWVTRHGA EPLPSEDENC TLVEVTEEEV ENSVKHIPSL
ATVILVKTMI RKRSFGNPFE GSRREERSLS APGNLLTKKP TREWEPLSEP KEARQRRQPP
GPRASPCGGG GSALVKGGPC VESCGAPAPG SPPRTPPQQP EEAMEPE
