AKT3_RAT
ID AKT3_RAT Reviewed; 479 AA.
AC Q63484;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2006, sequence version 2.
DT 03-AUG-2022, entry version 164.
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 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 [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-454.
RC TISSUE=Brain;
RX PubMed=7488143; DOI=10.1006/bbrc.1995.2654;
RA Konishi H., Kuroda S., Tanaka M., Matsuzaki H., Ono Y., Kameyama K.,
RA Haga T., Kikkawa U.;
RT "Molecular cloning and characterization of a new member of the RAC protein
RT kinase family: association of the pleckstrin homology domain of three types
RT of RAC protein kinase with protein kinase C subspecies and beta gamma
RT subunits of G proteins.";
RL Biochem. Biophys. Res. Commun. 216:526-534(1995).
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 (By similarity). {ECO:0000250}.
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 (By similarity). Interacts with BTBD10 (By
CC similarity). {ECO:0000250|UniProtKB:Q9WUA6}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC Membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}.
CC Note=Membrane-associated after cell stimulation leading to its
CC translocation. {ECO:0000250}.
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 -!- 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; AABR03086280; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; D49836; BAA08637.1; -; mRNA.
DR PIR; JC4345; JC4345.
DR RefSeq; NP_113763.1; NM_031575.1.
DR AlphaFoldDB; Q63484; -.
DR SMR; Q63484; -.
DR BioGRID; 248064; 59.
DR STRING; 10116.ENSRNOP00000054688; -.
DR GlyGen; Q63484; 2 sites.
DR iPTMnet; Q63484; -.
DR PhosphoSitePlus; Q63484; -.
DR jPOST; Q63484; -.
DR PaxDb; Q63484; -.
DR PRIDE; Q63484; -.
DR GeneID; 29414; -.
DR KEGG; rno:29414; -.
DR UCSC; RGD:62390; rat.
DR CTD; 10000; -.
DR RGD; 62390; Akt3.
DR eggNOG; KOG0690; Eukaryota.
DR InParanoid; Q63484; -.
DR OrthoDB; 614710at2759; -.
DR PhylomeDB; Q63484; -.
DR BRENDA; 2.7.11.1; 5301.
DR Reactome; R-RNO-1257604; PIP3 activates AKT signaling.
DR Reactome; R-RNO-1358803; Downregulation of ERBB2:ERBB3 signaling.
DR Reactome; R-RNO-198323; AKT phosphorylates targets in the cytosol.
DR Reactome; R-RNO-198693; AKT phosphorylates targets in the nucleus.
DR Reactome; R-RNO-199418; Negative regulation of the PI3K/AKT network.
DR Reactome; R-RNO-211163; AKT-mediated inactivation of FOXO1A.
DR Reactome; R-RNO-389357; CD28 dependent PI3K/Akt signaling.
DR Reactome; R-RNO-389513; CTLA4 inhibitory signaling.
DR Reactome; R-RNO-392451; G beta:gamma signalling through PI3Kgamma.
DR Reactome; R-RNO-5218920; VEGFR2 mediated vascular permeability.
DR Reactome; R-RNO-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-RNO-6804757; Regulation of TP53 Degradation.
DR Reactome; R-RNO-6804758; Regulation of TP53 Activity through Acetylation.
DR Reactome; R-RNO-6804759; Regulation of TP53 Activity through Association with Co-factors.
DR Reactome; R-RNO-69202; Cyclin E associated events during G1/S transition.
DR Reactome; R-RNO-69656; Cyclin A:Cdk2-associated events at S phase entry.
DR Reactome; R-RNO-8876198; RAB GEFs exchange GTP for GDP on RABs.
DR Reactome; R-RNO-8948751; Regulation of PTEN stability and activity.
DR Reactome; R-RNO-9607240; FLT3 Signaling.
DR Reactome; R-RNO-9614399; Regulation of localization of FOXO transcription factors.
DR Reactome; R-RNO-9634638; Estrogen-dependent nuclear events downstream of ESR-membrane signaling.
DR Reactome; R-RNO-9755511; KEAP1-NFE2L2 pathway.
DR PRO; PR:Q63484; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IDA:RGD.
DR GO; GO:0005080; F:protein kinase C binding; IPI:RGD.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:RGD.
DR GO; GO:0048854; P:brain morphogenesis; ISO:RGD.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IMP:MGI.
DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; ISO:RGD.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0000002; P:mitochondrial genome maintenance; ISO:RGD.
DR GO; GO:2000773; P:negative regulation of cellular senescence; ISO:RGD.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISO:RGD.
DR GO; GO:1905653; P:positive regulation of artery morphogenesis; ISO:RGD.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; ISO:RGD.
DR GO; GO:0090050; P:positive regulation of cell migration involved in sprouting angiogenesis; ISO:RGD.
DR GO; GO:0045793; P:positive regulation of cell size; ISO:RGD.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; ISO:RGD.
DR GO; GO:0010765; P:positive regulation of sodium ion transport; IMP:MGI.
DR GO; GO:0032008; P:positive regulation of TOR signaling; ISO:RGD.
DR GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; ISO:RGD.
DR GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
DR GO; GO:0007165; P:signal transduction; ISO:RGD.
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 2: Evidence at transcript level;
KW Acetylation; ATP-binding; Cytoplasm; Disulfide bond; Glycoprotein; Kinase;
KW Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; 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_0000085613"
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 446..479
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 448..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 CONFLICT 452..454
FT /note="DDD -> CPL (in Ref. 2; BAA08637)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 479 AA; 55796 MW; D75D83A027B1A6B9 CRC64;
MSDVTIVKED 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 GGPDDPKEIM RHSFFSGVNW QDVYDKKLVP
PFKPQVTSET DTRYFDEEFT AQTITITPPE KDDDDGMDCM DNERRPHFPQ FSYSASGRE
