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Protein

RAC-gamma serine/threonine-protein kinase

Gene

Akt3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT3 is the least studied AKT isoform. It plays an important role in brain development and is crucial for the viability of malignant glioma cells. AKT3 isoform may also be the key molecule in up-regulation and down-regulation of MMP13 via IL13. Required for the coordination of mitochondrial biogenesis with growth factor-induced increases in cellular energy demands. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis.2 Publications

Caution

In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain.Curated

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Two specific sites, one in the kinase domain (Thr-305) and the other in the C-terminal regulatory region (Ser-472), need to be phosphorylated for its full activation. IGF-1 leads to the activation of AKT3, which may play a role in regulating cell survival.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei177ATPPROSITE-ProRule annotation1
Active sitei271Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi154 – 162ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.1 3474
ReactomeiR-MMU-1257604 PIP3 activates AKT signaling
R-MMU-1358803 Downregulation of ERBB2:ERBB3 signaling
R-MMU-198323 AKT phosphorylates targets in the cytosol
R-MMU-198693 AKT phosphorylates targets in the nucleus
R-MMU-199418 Negative regulation of the PI3K/AKT network
R-MMU-211163 AKT-mediated inactivation of FOXO1A
R-MMU-389357 CD28 dependent PI3K/Akt signaling
R-MMU-389513 CTLA4 inhibitory signaling
R-MMU-392451 G beta:gamma signalling through PI3Kgamma
R-MMU-5218920 VEGFR2 mediated vascular permeability
R-MMU-5628897 TP53 Regulates Metabolic Genes
R-MMU-6804757 Regulation of TP53 Degradation
R-MMU-6804758 Regulation of TP53 Activity through Acetylation
R-MMU-6804759 Regulation of TP53 Activity through Association with Co-factors
R-MMU-69202 Cyclin E associated events during G1/S transition
R-MMU-69656 Cyclin A:Cdk2-associated events at S phase entry
R-MMU-8876198 RAB GEFs exchange GTP for GDP on RABs
R-MMU-8948751 Regulation of PTEN stability and activity

Names & Taxonomyi

Protein namesi
Recommended name:
RAC-gamma serine/threonine-protein kinase (EC:2.7.11.1)
Alternative name(s):
Protein kinase Akt-3
Protein kinase B gamma
Short name:
PKB gamma
RAC-PK-gamma
Gene namesi
Name:Akt3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 1

Organism-specific databases

MGIiMGI:1345147 Akt3

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Disruption phenotypei

Results in the cytoplasmic accumulation of the master regulator of mitochondrial biogenesis, Ppargc1a, and a reduction in known Ppargc1a target genes, which leads to an abnormal mitochondrial phenotype in the brain tissue.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi219D → V: Enhances kinase activity and causes low seizure threshold, sporadic tonic-clonic seizures, brain enlargement and ectopic neurons in the dentate hilus and molecular layer of the hippocampus. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000856122 – 479RAC-gamma serine/threonine-protein kinaseAdd BLAST478

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Disulfide bondi59 ↔ 76By similarity
Disulfide bondi293 ↔ 307By similarity
Glycosylationi302O-linked (GlcNAc) threonineBy similarity1
Modified residuei305Phosphothreonine; by PDPK1By similarity1
Glycosylationi309O-linked (GlcNAc) threonineBy similarity1
Modified residuei447PhosphothreonineBy similarity1
Modified residuei472Phosphoserine; by PKC/PRKCZBy similarity1

Post-translational modificationi

Phosphorylation on Thr-305 and Ser-472 is required for full activity.
Ubiquitinated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome (By similarity).By similarity
O-GlcNAcylation at Thr-302 and Thr-309 inhibits activating phosphorylation at Thr-305 via disrupting the interaction between AKT and PDK1.By similarity

Keywords - PTMi

Acetylation, Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ9WUA6
PeptideAtlasiQ9WUA6
PRIDEiQ9WUA6

PTM databases

iPTMnetiQ9WUA6
PhosphoSitePlusiQ9WUA6

Expressioni

Tissue specificityi

Isoform 1 is expressed in prostate, testis, uterus and mammary gland and isoform 2 is expressed in prostate, testis and mammary gland.

Gene expression databases

BgeeiENSMUSG00000019699
CleanExiMM_AKT3
GenevisibleiQ9WUA6 MM

Interactioni

Subunit structurei

Interacts (via PH domain) with TCL1A; this enhances AKT3 phosphorylation and activation. Interacts with TRAF6 (By similarity). Interacts with KCTD20 (PubMed:24156551). Interacts with BTBD10 (PubMed:18160256).By similarity2 Publications

Protein-protein interaction databases

BioGridi204720, 2 interactors
IntActiQ9WUA6, 1 interactor
MINTiQ9WUA6
STRINGi10090.ENSMUSP00000106789

Structurei

3D structure databases

ProteinModelPortaliQ9WUA6
SMRiQ9WUA6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini5 – 107PHPROSITE-ProRule annotationAdd BLAST103
Domaini148 – 405Protein kinasePROSITE-ProRule annotationAdd BLAST258
Domaini406 – 479AGC-kinase C-terminalAdd BLAST74

Domaini

Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PI3K) results in its targeting to the plasma membrane.

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0598 Eukaryota
ENOG410XNPH LUCA
GeneTreeiENSGT00890000139324
HOGENOMiHOG000233033
HOVERGENiHBG108317
InParanoidiQ9WUA6
KOiK04456
OMAiCQIMSVD
OrthoDBiEOG091G06FF
PhylomeDBiQ9WUA6
TreeFamiTF102004

Family and domain databases

CDDicd05593 STKc_PKB_gamma, 1 hit
Gene3Di2.30.29.30, 1 hit
InterProiView protein in InterPro
IPR000961 AGC-kinase_C
IPR034675 Akt3
IPR011009 Kinase-like_dom_sf
IPR011993 PH-like_dom_sf
IPR001849 PH_domain
IPR017892 Pkinase_C
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00169 PH, 1 hit
PF00069 Pkinase, 1 hit
PF00433 Pkinase_C, 1 hit
SMARTiView protein in SMART
SM00233 PH, 1 hit
SM00133 S_TK_X, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS51285 AGC_KINASE_CTER, 1 hit
PS50003 PH_DOMAIN, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9WUA6-1) [UniParc]FASTAAdd to basket
Also known as: PKB gamma

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSDVTIVKEG WVQKRGEYIK NWRPRYFLLK TDGSFIGYKE KPQDVDLPYP
60 70 80 90 100
LNNFSVAKCQ LMKTERPKPN TFIIRCLQWT TVIERTFHVD TPEEREEWTE
110 120 130 140 150
AIQAVADRLQ RQEEERMNCS PTSQIDNIGE EEMDASTTHH KRKTMNDFDY
160 170 180 190 200
LKLLGKGTFG KVILVREKAS GKYYAMKILK KEVIIAKDEV AHTLTESRVL
210 220 230 240 250
KNTRHPFLTS LKYSFQTKDR LCFVMEYVNG GELFFHLSRE RVFSEDRTRF
260 270 280 290 300
YGAEIVSALD YLHSGKIVYR DLKLENLMLD KDGHIKITDF GLCKEGITDA
310 320 330 340 350
ATMKTFCGTP EYLAPEVLED NDYGRAVDWW GLGVVMYEMM CGRLPFYNQD
360 370 380 390 400
HEKLFELILM EDIKFPRTLS SDAKSLLSGL LIKDPNKRLG GGPDDAKEIM
410 420 430 440 450
RHSFFSGVNW QDVYDKKLVP PFKPQVTSET DTRYFDEEFT AQTITITPPE
460 470
KYDDDGMDGM DNERRPHFPQ FSYSASGRE
Length:479
Mass (Da):55,714
Last modified:November 1, 1999 - v1
Checksum:iF08ACDF75743B8FB
GO
Isoform 2 (identifier: Q9WUA6-2) [UniParc]FASTAAdd to basket
Also known as: PKB gamma 1

The sequence of this isoform differs from the canonical sequence as follows:
     452-479: YDDDGMDGMDNERRPHFPQFSYSASGRE → CQQSDCGMLGNWKKNDNKK

Show »
Length:470
Mass (Da):54,631
Checksum:iB4352DF496792EF8
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_004948452 – 479YDDDG…ASGRE → CQQSDCGMLGNWKKNDNKK in isoform 2. 1 PublicationAdd BLAST28

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF124142 mRNA Translation: AAD29090.1
CCDSiCCDS35799.1 [Q9WUA6-1]
RefSeqiNP_035915.3, NM_011785.3 [Q9WUA6-1]
XP_006496881.1, XM_006496818.3 [Q9WUA6-1]
XP_006496882.1, XM_006496819.3 [Q9WUA6-1]
UniGeneiMm.235194

Genome annotation databases

EnsembliENSMUST00000019843; ENSMUSP00000019843; ENSMUSG00000019699 [Q9WUA6-2]
ENSMUST00000111159; ENSMUSP00000106789; ENSMUSG00000019699 [Q9WUA6-1]
ENSMUST00000111160; ENSMUSP00000106790; ENSMUSG00000019699 [Q9WUA6-1]
GeneIDi23797
KEGGimmu:23797
UCSCiuc007duk.2 mouse [Q9WUA6-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiAKT3_MOUSE
AccessioniPrimary (citable) accession number: Q9WUA6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: November 1, 1999
Last modified: May 23, 2018
This is version 167 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

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