AKT3_MOUSE
ID AKT3_MOUSE Reviewed; 479 AA.
AC Q9WUA6;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 193.
DE RecName: Full=RAC-gamma serine/threonine-protein kinase;
DE EC=2.7.11.1;
DE AltName: Full=Protein kinase Akt-3;
DE AltName: Full=Protein kinase B gamma;
DE Short=PKB gamma;
DE AltName: Full=RAC-PK-gamma;
GN Name=Akt3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10092583; DOI=10.1074/jbc.274.14.9133;
RA Brodbeck D., Cron P., Hemmings B.A.;
RT "A human protein kinase B gamma with regulatory phosphorylation sites in
RT the activation loop and in the C-terminal hydrophobic domain.";
RL J. Biol. Chem. 274:9133-9136(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain;
RX PubMed=11387345; DOI=10.1074/jbc.m104633200;
RA Brodbeck D., Hill M.M., Hemmings B.A.;
RT "Two splice variants of PKB gamma have different regulatory capacity
RT depending on the presence or absence of the regulatory phosphorylation site
RT Ser-472 in the C-terminal hydrophobic domain.";
RL J. Biol. Chem. 276:29550-29558(2001).
RN [3]
RP FUNCTION.
RX PubMed=15713641; DOI=10.1128/mcb.25.5.1869-1878.2005;
RA Easton R.M., Cho H., Roovers K., Shineman D.W., Mizrahi M., Forman M.S.,
RA Lee V.M., Szabolcs M., de Jong R., Oltersdorf T., Ludwig T.,
RA Efstratiadis A., Birnbaum M.J.;
RT "Role for Akt3/protein kinase Bgamma in attainment of normal brain size.";
RL Mol. Cell. Biol. 25:1869-1878(2005).
RN [4]
RP INTERACTION WITH BTBD10.
RX PubMed=18160256; DOI=10.1016/j.cellsig.2007.11.004;
RA Nawa M., Kanekura K., Hashimoto Y., Aiso S., Matsuoka M.;
RT "A novel Akt/PKB-interacting protein promotes cell adhesion and inhibits
RT familial amyotrophic lateral sclerosis-linked mutant SOD1-induced neuronal
RT death via inhibition of PP2A-mediated dephosphorylation of Akt/PKB.";
RL Cell. Signal. 20:493-505(2008).
RN [5]
RP DISRUPTION PHENOTYPE.
RX PubMed=18524868; DOI=10.1096/fj.08-106468;
RA Wright G.L., Maroulakou I.G., Eldridge J., Liby T.L., Sridharan V.,
RA Tsichlis P.N., Muise-Helmericks R.C.;
RT "VEGF stimulation of mitochondrial biogenesis: requirement of AKT3
RT kinase.";
RL FASEB J. 22:3264-3275(2008).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP MUTAGENESIS OF ASP-219, AND FUNCTION.
RX PubMed=21159799; DOI=10.1093/hmg/ddq544;
RA Tokuda S., Mahaffey C.L., Monks B., Faulkner C.R., Birnbaum M.J.,
RA Danzer S.C., Frankel W.N.;
RT "A novel Akt3 mutation associated with enhanced kinase activity and seizure
RT susceptibility in mice.";
RL Hum. Mol. Genet. 20:988-999(2011).
RN [8]
RP REVIEW ON FUNCTION.
RX PubMed=21620960; DOI=10.1016/j.cellsig.2011.05.004;
RA Hers I., Vincent E.E., Tavare J.M.;
RT "Akt signalling in health and disease.";
RL Cell. Signal. 23:1515-1527(2011).
RN [9]
RP INTERACTION WITH KCTD20.
RX PubMed=24156551; DOI=10.1186/1471-2091-14-27;
RA Nawa M., Matsuoka M.;
RT "KCTD20, a relative of BTBD10, is a positive regulator of Akt.";
RL BMC Biochem. 14:27-27(2013).
CC -!- FUNCTION: AKT3 is one of 3 closely related serine/threonine-protein
CC kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate
CC many processes including metabolism, proliferation, cell survival,
CC growth and angiogenesis. This is mediated through serine and/or
CC threonine phosphorylation of a range of downstream substrates. Over 100
CC substrate candidates have been reported so far, but for most of them,
CC no isoform specificity has been reported. AKT3 is the least studied AKT
CC isoform. It plays an important role in brain development and is crucial
CC for the viability of malignant glioma cells. AKT3 isoform may also be
CC the key molecule in up-regulation and down-regulation of MMP13 via
CC IL13. Required for the coordination of mitochondrial biogenesis with
CC growth factor-induced increases in cellular energy demands. Down-
CC regulation by RNA interference reduces the expression of the
CC phosphorylated form of BAD, resulting in the induction of caspase-
CC dependent apoptosis. {ECO:0000269|PubMed:15713641,
CC ECO:0000269|PubMed:21159799}.
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=2.7.11.1;
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=2.7.11.1;
CC -!- ACTIVITY REGULATION: Two specific sites, one in the kinase domain (Thr-
CC 305) and the other in the C-terminal regulatory region (Ser-472), need
CC to be phosphorylated for its full activation. IGF-1 leads to the
CC activation of AKT3, which may play a role in regulating cell survival.
CC {ECO:0000250}.
CC -!- SUBUNIT: Interacts (via PH domain) with TCL1A; this enhances AKT3
CC phosphorylation and activation. Interacts with TRAF6 (By similarity).
CC Interacts with KCTD20 (PubMed:24156551). Interacts with BTBD10
CC (PubMed:18160256). {ECO:0000250, ECO:0000269|PubMed:18160256,
CC ECO:0000269|PubMed:24156551}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm. Membrane;
CC Peripheral membrane protein. Note=Membrane-associated after cell
CC stimulation leading to its translocation.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=PKB gamma;
CC IsoId=Q9WUA6-1; Sequence=Displayed;
CC Name=2; Synonyms=PKB gamma 1;
CC IsoId=Q9WUA6-2; Sequence=VSP_004948;
CC -!- TISSUE SPECIFICITY: Isoform 1 is expressed in prostate, testis, uterus
CC and mammary gland and isoform 2 is expressed in prostate, testis and
CC mammary gland.
CC -!- DOMAIN: Binding of the PH domain to the phosphatidylinositol 3-kinase
CC alpha (PI(3)K) results in its targeting to the plasma membrane.
CC -!- PTM: Phosphorylation on Thr-305 and Ser-472 is required for full
CC activity.
CC -!- PTM: Ubiquitinated. When fully phosphorylated and translocated into the
CC nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3,
CC leading to its degradation by the proteasome (By similarity).
CC {ECO:0000250}.
CC -!- PTM: O-GlcNAcylation at Thr-302 and Thr-309 inhibits activating
CC phosphorylation at Thr-305 via disrupting the interaction between AKT
CC and PDK1. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Results in the cytoplasmic accumulation of the
CC master regulator of mitochondrial biogenesis, Ppargc1a, and a reduction
CC in known Ppargc1a target genes, which leads to an abnormal
CC mitochondrial phenotype in the brain tissue.
CC {ECO:0000269|PubMed:18524868}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. RAC subfamily. {ECO:0000305}.
CC -!- CAUTION: In light of strong homologies in the primary amino acid
CC sequence, the 3 AKT kinases were long surmised to play redundant and
CC overlapping roles. More recent studies has brought into question the
CC redundancy within AKT kinase isoforms and instead pointed to isoform
CC specific functions in different cellular events and diseases. AKT1 is
CC more specifically involved in cellular survival pathways, by inhibiting
CC apoptotic processes; whereas AKT2 is more specific for the insulin
CC receptor signaling pathway. Moreover, while AKT1 and AKT2 are often
CC implicated in many aspects of cellular transformation, the 2 isoforms
CC act in a complementary opposing manner. The role of AKT3 is less clear,
CC though it appears to be predominantly expressed in brain.
CC {ECO:0000305}.
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DR EMBL; AF124142; AAD29090.1; -; mRNA.
DR CCDS; CCDS35799.1; -. [Q9WUA6-1]
DR RefSeq; NP_035915.3; NM_011785.3. [Q9WUA6-1]
DR RefSeq; XP_006496881.1; XM_006496818.3. [Q9WUA6-1]
DR RefSeq; XP_006496882.1; XM_006496819.3. [Q9WUA6-1]
DR AlphaFoldDB; Q9WUA6; -.
DR SMR; Q9WUA6; -.
DR BioGRID; 204720; 10.
DR STRING; 10090.ENSMUSP00000106789; -.
DR GlyGen; Q9WUA6; 2 sites.
DR iPTMnet; Q9WUA6; -.
DR PhosphoSitePlus; Q9WUA6; -.
DR jPOST; Q9WUA6; -.
DR MaxQB; Q9WUA6; -.
DR PaxDb; Q9WUA6; -.
DR PeptideAtlas; Q9WUA6; -.
DR PRIDE; Q9WUA6; -.
DR ProteomicsDB; 296017; -. [Q9WUA6-1]
DR ProteomicsDB; 296018; -. [Q9WUA6-2]
DR Antibodypedia; 3402; 1176 antibodies from 46 providers.
DR DNASU; 23797; -.
DR Ensembl; ENSMUST00000019843; ENSMUSP00000019843; ENSMUSG00000019699. [Q9WUA6-2]
DR Ensembl; ENSMUST00000111159; ENSMUSP00000106789; ENSMUSG00000019699. [Q9WUA6-1]
DR Ensembl; ENSMUST00000111160; ENSMUSP00000106790; ENSMUSG00000019699. [Q9WUA6-1]
DR GeneID; 23797; -.
DR KEGG; mmu:23797; -.
DR UCSC; uc007duk.2; mouse. [Q9WUA6-1]
DR CTD; 10000; -.
DR MGI; MGI:1345147; Akt3.
DR VEuPathDB; HostDB:ENSMUSG00000019699; -.
DR eggNOG; KOG0690; Eukaryota.
DR GeneTree; ENSGT00940000157060; -.
DR HOGENOM; CLU_000288_11_0_1; -.
DR InParanoid; Q9WUA6; -.
DR OMA; RGCQIMA; -.
DR PhylomeDB; Q9WUA6; -.
DR TreeFam; TF102004; -.
DR BRENDA; 2.7.11.1; 3474.
DR Reactome; R-MMU-1257604; PIP3 activates AKT signaling.
DR Reactome; R-MMU-1358803; Downregulation of ERBB2:ERBB3 signaling.
DR Reactome; R-MMU-198323; AKT phosphorylates targets in the cytosol.
DR Reactome; R-MMU-198693; AKT phosphorylates targets in the nucleus.
DR Reactome; R-MMU-199418; Negative regulation of the PI3K/AKT network.
DR Reactome; R-MMU-211163; AKT-mediated inactivation of FOXO1A.
DR Reactome; R-MMU-389357; CD28 dependent PI3K/Akt signaling.
DR Reactome; R-MMU-389513; CTLA4 inhibitory signaling.
DR Reactome; R-MMU-392451; G beta:gamma signalling through PI3Kgamma.
DR Reactome; R-MMU-5218920; VEGFR2 mediated vascular permeability.
DR Reactome; R-MMU-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-MMU-6804757; Regulation of TP53 Degradation.
DR Reactome; R-MMU-6804758; Regulation of TP53 Activity through Acetylation.
DR Reactome; R-MMU-6804759; Regulation of TP53 Activity through Association with Co-factors.
DR Reactome; R-MMU-69202; Cyclin E associated events during G1/S transition.
DR Reactome; R-MMU-69656; Cyclin A:Cdk2-associated events at S phase entry.
DR Reactome; R-MMU-8876198; RAB GEFs exchange GTP for GDP on RABs.
DR Reactome; R-MMU-8948751; Regulation of PTEN stability and activity.
DR Reactome; R-MMU-9607240; FLT3 Signaling.
DR Reactome; R-MMU-9614399; Regulation of localization of FOXO transcription factors.
DR Reactome; R-MMU-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling.
DR Reactome; R-MMU-9755511; KEAP1-NFE2L2 pathway.
DR BioGRID-ORCS; 23797; 4 hits in 75 CRISPR screens.
DR ChiTaRS; Akt3; mouse.
DR PRO; PR:Q9WUA6; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; Q9WUA6; protein.
DR Bgee; ENSMUSG00000019699; Expressed in cortical plate and 231 other tissues.
DR Genevisible; Q9WUA6; MM.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; ISO:MGI.
DR GO; GO:0004672; F:protein kinase activity; ISO:MGI.
DR GO; GO:0005080; F:protein kinase C binding; ISO:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:MGI.
DR GO; GO:0048854; P:brain morphogenesis; IMP:MGI.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISO:MGI.
DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; IMP:MGI.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0000002; P:mitochondrial genome maintenance; ISO:MGI.
DR GO; GO:2000773; P:negative regulation of cellular senescence; ISO:MGI.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISO:MGI.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISO:MGI.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:BHF-UCL.
DR GO; GO:1905653; P:positive regulation of artery morphogenesis; IMP:BHF-UCL.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; ISO:MGI.
DR GO; GO:0090050; P:positive regulation of cell migration involved in sprouting angiogenesis; ISO:MGI.
DR GO; GO:0045793; P:positive regulation of cell size; IMP:MGI.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; ISO:MGI.
DR GO; GO:0010765; P:positive regulation of sodium ion transport; ISO:MGI.
DR GO; GO:0032008; P:positive regulation of TOR signaling; IMP:MGI.
DR GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR GO; GO:0007165; P:signal transduction; ISO:MGI.
DR CDD; cd01241; PH_PKB; 1.
DR CDD; cd05593; STKc_PKB_gamma; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR034675; Akt3.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR039026; PH_PKB.
DR InterPro; IPR017892; Pkinase_C.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR039029; RAC_gamma-like.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR24351:SF199; PTHR24351:SF199; 1.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00433; Pkinase_C; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS50003; PH_DOMAIN; 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; Cytoplasm; Disulfide bond;
KW Glycoprotein; Kinase; Membrane; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q9Y243"
FT CHAIN 2..479
FT /note="RAC-gamma serine/threonine-protein kinase"
FT /id="PRO_0000085612"
FT DOMAIN 5..107
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 148..405
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 406..479
FT /note="AGC-kinase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT REGION 445..479
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 451..465
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 271
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 154..162
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 177
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:Q9Y243"
FT MOD_RES 305
FT /note="Phosphothreonine; by PDPK1"
FT /evidence="ECO:0000250|UniProtKB:Q9Y243"
FT MOD_RES 447
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y243"
FT MOD_RES 472
FT /note="Phosphoserine; by PKC/PRKCZ"
FT /evidence="ECO:0000250|UniProtKB:Q9Y243"
FT CARBOHYD 302
FT /note="O-linked (GlcNAc) threonine"
FT /evidence="ECO:0000250"
FT CARBOHYD 309
FT /note="O-linked (GlcNAc) threonine"
FT /evidence="ECO:0000250"
FT DISULFID 59..76
FT /evidence="ECO:0000250"
FT DISULFID 293..307
FT /evidence="ECO:0000250"
FT VAR_SEQ 452..479
FT /note="YDDDGMDGMDNERRPHFPQFSYSASGRE -> CQQSDCGMLGNWKKNDNKK
FT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11387345"
FT /id="VSP_004948"
FT MUTAGEN 219
FT /note="D->V: Enhances kinase activity and causes low
FT seizure threshold, sporadic tonic-clonic seizures, brain
FT enlargement and ectopic neurons in the dentate hilus and
FT molecular layer of the hippocampus."
FT /evidence="ECO:0000269|PubMed:21159799"
SQ SEQUENCE 479 AA; 55714 MW; F08ACDF75743B8FB CRC64;
MSDVTIVKEG WVQKRGEYIK NWRPRYFLLK TDGSFIGYKE KPQDVDLPYP LNNFSVAKCQ
LMKTERPKPN TFIIRCLQWT TVIERTFHVD TPEEREEWTE AIQAVADRLQ RQEEERMNCS
PTSQIDNIGE EEMDASTTHH KRKTMNDFDY LKLLGKGTFG KVILVREKAS GKYYAMKILK
KEVIIAKDEV AHTLTESRVL KNTRHPFLTS LKYSFQTKDR LCFVMEYVNG GELFFHLSRE
RVFSEDRTRF YGAEIVSALD YLHSGKIVYR DLKLENLMLD KDGHIKITDF GLCKEGITDA
ATMKTFCGTP EYLAPEVLED NDYGRAVDWW GLGVVMYEMM CGRLPFYNQD HEKLFELILM
EDIKFPRTLS SDAKSLLSGL LIKDPNKRLG GGPDDAKEIM RHSFFSGVNW QDVYDKKLVP
PFKPQVTSET DTRYFDEEFT AQTITITPPE KYDDDGMDGM DNERRPHFPQ FSYSASGRE
