Q9WUA6 (AKT3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:

Akt3

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	479 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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 alignant 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. Ref.3 Ref.5
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	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 By similarity. IGF-1 leads to the activation of AKT3, which may play a role in regulating cell survival By similarity.
Subunit structure	Interacts (via PH domain) with TCL1A; this enhances AKT3 phosphorylation and activation. Interacts with TRAF6 By similarity.
Subcellular location	Nucleus By similarity. Cytoplasm. Membrane; Peripheral membrane protein. Note: Membrane-associated after cell stimulation leading to its translocation.
Tissue specificity	Isoform 1 is expressed in prostate, testis, uterus and mammary gland and isoform 2 is expressed in prostate, testis and mammary gland.
Domain	Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PI3K) results in its targeting to the plasma membrane.
Post-translational modification	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. O-GlcNAcylation at Thr-302 and Thr-309 inhibits activating phosphorylation at Thr-305 via disrupting the interaction between AKT and PDK1 By similarity.
Disruption phenotype	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. Ref.4
Sequence similarities	Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily. Contains 1 AGC-kinase C-terminal domain. Contains 1 PH domain. Contains 1 protein kinase domain.
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.

Ontologies

Keywords
Cellular component	Cytoplasm Membrane Nucleus
Coding sequence diversity	Alternative splicing
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Disulfide bond Glycoprotein Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cellular response to insulin stimulus Inferred from sequence orthology Ref.1. Source: MGI mitochondrial genome maintenance Inferred from electronic annotation. Source: Compara peptidyl-serine phosphorylation Inferred from sequence orthology Ref.1. Source: MGI peptidyl-threonine phosphorylation Inferred from sequence orthology Ref.1. Source: MGI signal transduction Inferred from electronic annotation. Source: Compara
Cellular_component	Golgi apparatus Inferred from electronic annotation. Source: Compara nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW phospholipid binding Inferred from electronic annotation. Source: InterPro protein kinase activity Inferred from sequence orthology Ref.1. Source: MGI protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9WUA6-1)

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.

Isoform 2 (identifier: Q9WUA6-2)

Also known as: PKB gamma 1;

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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 479	479	RAC-gamma serine/threonine-protein kinase		PRO_0000085612
Regions
	Domain	5 – 107	103	PH
	Domain	148 – 405	258	Protein kinase
	Domain	406 – 479	74	AGC-kinase C-terminal
	Nucleotide binding	154 – 162	9	ATP By similarity
Sites
	Active site	271	1	Proton acceptor By similarity
	Binding site	177	1	ATP By similarity
Amino acid modifications
	Modified residue	305	1	Phosphothreonine; by PDPK1 By similarity
	Modified residue	472	1	Phosphoserine; by PKC/PRKCZ By similarity
	Glycosylation	302	1	O-linked (GlcNAc...) By similarity
	Glycosylation	309	1	O-linked (GlcNAc...) By similarity
	Disulfide bond	59 ↔ 76		By similarity
	Disulfide bond	293 ↔ 307		By similarity
Natural variations
	Alternative sequence	452 – 479	28	YDDDG…ASGRE → CQQSDCGMLGNWKKNDNKK in isoform 2.		VSP_004948
Experimental info
	Mutagenesis	219	1	D → 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. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (PKB gamma) [UniParc]. Last modified November 1, 1999. Version 1. Checksum: F08ACDF75743B8FB	FASTA	479	55,714
	10 20 30 40 50 60 MSDVTIVKEG WVQKRGEYIK NWRPRYFLLK TDGSFIGYKE KPQDVDLPYP LNNFSVAKCQ 70 80 90 100 110 120 LMKTERPKPN TFIIRCLQWT TVIERTFHVD TPEEREEWTE AIQAVADRLQ RQEEERMNCS 130 140 150 160 170 180 PTSQIDNIGE EEMDASTTHH KRKTMNDFDY LKLLGKGTFG KVILVREKAS GKYYAMKILK 190 200 210 220 230 240 KEVIIAKDEV AHTLTESRVL KNTRHPFLTS LKYSFQTKDR LCFVMEYVNG GELFFHLSRE 250 260 270 280 290 300 RVFSEDRTRF YGAEIVSALD YLHSGKIVYR DLKLENLMLD KDGHIKITDF GLCKEGITDA 310 320 330 340 350 360 ATMKTFCGTP EYLAPEVLED NDYGRAVDWW GLGVVMYEMM CGRLPFYNQD HEKLFELILM 370 380 390 400 410 420 EDIKFPRTLS SDAKSLLSGL LIKDPNKRLG GGPDDAKEIM RHSFFSGVNW QDVYDKKLVP 430 440 450 460 470 PFKPQVTSET DTRYFDEEFT AQTITITPPE KYDDDGMDGM DNERRPHFPQ FSYSASGRE
	Isoform 2 (PKB gamma 1) [UniParc]. Checksum: B4352DF496792EF8	FASTA	470	54,631
	10 20 30 40 50 60 MSDVTIVKEG WVQKRGEYIK NWRPRYFLLK TDGSFIGYKE KPQDVDLPYP LNNFSVAKCQ 70 80 90 100 110 120 LMKTERPKPN TFIIRCLQWT TVIERTFHVD TPEEREEWTE AIQAVADRLQ RQEEERMNCS 130 140 150 160 170 180 PTSQIDNIGE EEMDASTTHH KRKTMNDFDY LKLLGKGTFG KVILVREKAS GKYYAMKILK 190 200 210 220 230 240 KEVIIAKDEV AHTLTESRVL KNTRHPFLTS LKYSFQTKDR LCFVMEYVNG GELFFHLSRE 250 260 270 280 290 300 RVFSEDRTRF YGAEIVSALD YLHSGKIVYR DLKLENLMLD KDGHIKITDF GLCKEGITDA 310 320 330 340 350 360 ATMKTFCGTP EYLAPEVLED NDYGRAVDWW GLGVVMYEMM CGRLPFYNQD HEKLFELILM 370 380 390 400 410 420 EDIKFPRTLS SDAKSLLSGL LIKDPNKRLG GGPDDAKEIM RHSFFSGVNW QDVYDKKLVP 430 440 450 460 470 PFKPQVTSET DTRYFDEEFT AQTITITPPE KCQQSDCGML GNWKKNDNKK

References

[1]	"A human protein kinase B gamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain." Brodbeck D., Cron P., Hemmings B.A. J. Biol. Chem. 274:9133-9136(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Two splice variants of PKB gamma have different regulatory capacity depending on the presence or absence of the regulatory phosphorylation site Ser-472 in the C-terminal hydrophobic domain." Brodbeck D., Hill M.M., Hemmings B.A. J. Biol. Chem. 276:29550-29558(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). Tissue: Brain.
[3]	"Role for Akt3/protein kinase Bgamma in attainment of normal brain size." Easton R.M., Cho H., Roovers K., Shineman D.W., Mizrahi M., Forman M.S., Lee V.M., Szabolcs M., de Jong R., Oltersdorf T., Ludwig T., Efstratiadis A., Birnbaum M.J. Mol. Cell. Biol. 25:1869-1878(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[4]	"VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase." Wright G.L., Maroulakou I.G., Eldridge J., Liby T.L., Sridharan V., Tsichlis P.N., Muise-Helmericks R.C. FASEB J. 22:3264-3275(2008) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[5]	"A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice." Tokuda S., Mahaffey C.L., Monks B., Faulkner C.R., Birnbaum M.J., Danzer S.C., Frankel W.N. Hum. Mol. Genet. 20:988-999(2011) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF ASP-219, FUNCTION.
[6]	"Akt signalling in health and disease." Hers I., Vincent E.E., Tavare J.M. Cell. Signal. 23:1515-1527(2011) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF124142 mRNA. Translation: AAD29090.1.
IPI	IPI00124450. IPI00228306.
RefSeq	NP_035915.3. NM_011785.3.
UniGene	Mm.235194.
3D structure databases
ProteinModelPortal	Q9WUA6.
SMR	Q9WUA6. Positions 3-476.
ModBase	Search...
Protein-protein interaction databases
STRING	10090.ENSMUSP00000106790.
PTM databases
PhosphoSite	Q9WUA6.
Proteomic databases
PaxDb	Q9WUA6.
PRIDE	Q9WUA6.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000019843; ENSMUSP00000019843; ENSMUSG00000019699. ENSMUST00000111159; ENSMUSP00000106789; ENSMUSG00000019699. ENSMUST00000111160; ENSMUSP00000106790; ENSMUSG00000019699.
GeneID	23797.
KEGG	mmu:23797.
UCSC	uc007duk.2. mouse.
Organism-specific databases
CTD	10000.
MGI	MGI:1345147. Akt3.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00700000104409.
HOGENOM	HOG000233033.
HOVERGEN	HBG108317.
InParanoid	Q9WUA6.
KO	K04456.
OMA	IMSDVTI.
OrthoDB	EOG40GCQP.
Enzyme and pathway databases
BRENDA	2.7.11.1. 3474.
Gene expression databases
Bgee	Q9WUA6.
CleanEx	MM_AKT3.
Genevestigator	Q9WUA6.
GermOnline	ENSMUSG00000019699. Mus musculus.
Family and domain databases
Gene3D	2.30.29.30. 1 hit.
InterPro	IPR000961. AGC-kinase_C. IPR011009. Kinase-like_dom. IPR011993. PH_like_dom. IPR017892. Pkinase_C. IPR001849. Pleckstrin_homology. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00169. PH. 1 hit. PF00069. Pkinase. 1 hit. PF00433. Pkinase_C. 1 hit. [Graphical view]
SMART	SM00233. PH. 1 hit. SM00133. S_TK_X. 1 hit. SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
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. [Graphical view]
ProtoNet	Search...
Other
NextBio	303415.
SOURCE	Search...

Entry information

Entry name

AKT3_MOUSE

Accession

Primary (citable) accession number: Q9WUA6

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	November 1, 1999
Last modified:	April 3, 2013
This is version 121 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program