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Q60823 (AKT2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 130. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
RAC-beta serine/threonine-protein kinase

EC=2.7.11.1
Alternative name(s):
Protein kinase Akt-2
Protein kinase B beta
Short name=PKB beta
RAC-PK-beta
Gene names
Name:Akt2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length481 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

AKT2 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinases, 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 specificityhas been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform ofcyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI3P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI3K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Ref.3 Ref.4

One of the few specific substrates of AKT2 identified so far is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsibleof the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. Phosphorylates CLK2 on 'Thr-343'. Ref.3 Ref.4

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

Two specific sites, one in the kinase domain (Thr-309) and the other in the C-terminal regulatory region (Ser-474), need to be phosphorylated for its full activation By similarity.

Subunit structure

Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CLK2, PBH2 and TRAF6. Interacts (when phosphorylated) with CLIP3, the interaction promotes cell membrane localization By similarity.

Subcellular location

Cytoplasm By similarity. Nucleus By similarity. Cell membrane; Peripheral membrane protein By similarity. Note: Localizes within both nucleus and cytoplasm of proliferative primary myoblasts and mostly within the nucleus of differentiated primary myoblasts By similarity. By virtue of the N-terminal PH domain, is recruited to sites of the plasma membrane containing increased PI(3,4,5)P3 or PI(3,4)P2, cell membrane targeting is also facilitared by interaction with CLIP3 By similarity.

Domain

Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PIK3CA) results in its targeting to the plasma membrane By similarity.

Post-translational modification

Phosphorylation on Thr-309 and Ser-474 is required for full activity By similarity.

Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT2 ubiquitination. 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-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via disrupting the interaction between AKT and PDK1 By similarity.

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 specificfunctions 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
   Biological processApoptosis
Carbohydrate metabolism
Glucose metabolism
Glycogen biosynthesis
Glycogen metabolism
Sugar transport
Translation regulation
Transport
   Cellular componentCell membrane
Cytoplasm
Membrane
Nucleus
   LigandATP-binding
Nucleotide-binding
   Molecular functionDevelopmental protein
Kinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Disulfide bond
Glycoprotein
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of Ral GTPase activity

Inferred from genetic interaction PubMed 21148297. Source: MGI

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

carbohydrate transport

Inferred from electronic annotation. Source: UniProtKB-KW

cellular response to insulin stimulus

Inferred from direct assay Ref.4. Source: UniProtKB

glucose metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

glycogen biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-KW

insulin receptor signaling pathway

Inferred from direct assay PubMed 21148297. Source: MGI

intracellular protein transmembrane transport

Inferred from mutant phenotype Ref.4. Source: UniProtKB

negative regulation of plasma membrane long-chain fatty acid transport

Inferred from electronic annotation. Source: Ensembl

peripheral nervous system myelin maintenance

Inferred from mutant phenotype PubMed 20448149. Source: MGI

positive regulation of cell motility

Inferred from electronic annotation. Source: Ensembl

positive regulation of fatty acid beta-oxidation

Inferred from electronic annotation. Source: Ensembl

positive regulation of glucose import in response to insulin stimulus

Inferred from genetic interaction Ref.4. Source: MGI

positive regulation of glycogen biosynthetic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein phosphorylation

Inferred from direct assay Ref.4. Source: UniProtKB

positive regulation of protein targeting to membrane

Inferred from mutant phenotype Ref.4. Source: UniProtKB

positive regulation of vesicle fusion

Inferred from mutant phenotype Ref.4. Source: UniProtKB

protein localization to plasma membrane

Inferred from genetic interaction Ref.4. Source: MGI

protein phosphorylation

Inferred from direct assay Ref.4. Source: MGI

regulation of translation

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcell cortex

Inferred from mutant phenotype Ref.4. Source: UniProtKB

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

plasma membrane

Inferred from mutant phenotype Ref.4. Source: UniProtKB

ruffle membrane

Inferred from mutant phenotype Ref.4. Source: UniProtKB

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction PubMed 12791994PubMed 19139280PubMed 21737686. Source: UniProtKB

protein kinase activity

Inferred from direct assay Ref.4. Source: MGI

protein serine/threonine kinase activity

Inferred from direct assay PubMed 21148297. Source: MGI

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 481481RAC-beta serine/threonine-protein kinase
PRO_0000085609

Regions

Domain5 – 108104PH
Domain152 – 409258Protein kinase
Domain410 – 48172AGC-kinase C-terminal
Nucleotide binding158 – 1669ATP By similarity
Region230 – 2323Inhibitor binding By similarity
Region277 – 2793Inhibitor binding By similarity
Region292 – 2932Inhibitor binding By similarity

Sites

Active site2751Proton acceptor By similarity
Binding site1811ATP By similarity
Binding site1811Inhibitor By similarity
Binding site2001Inhibitor By similarity
Binding site2321Inhibitor; via amide nitrogen By similarity
Binding site2361Inhibitor By similarity
Binding site2791Inhibitor; via carbonyl oxygen[2X39] By similarity
Binding site2801Manganese By similarity
Binding site2931Inhibitor By similarity
Binding site2931Manganese By similarity
Binding site2941Inhibitor; via amide nitrogen By similarity

Amino acid modifications

Modified residue11N-acetylmethionine By similarity
Modified residue1261Phosphoserine By similarity
Modified residue3091Phosphothreonine; by PDPK1 By similarity
Modified residue4471Phosphoserine By similarity
Modified residue4511Phosphothreonine By similarity
Modified residue4741Phosphoserine By similarity
Modified residue4781Phosphoserine By similarity
Glycosylation1281O-linked (GlcNAc) By similarity
Glycosylation1311O-linked (GlcNAc) By similarity
Glycosylation3061O-linked (GlcNAc) By similarity
Glycosylation3131O-linked (GlcNAc) By similarity
Disulfide bond60 ↔ 77 By similarity
Disulfide bond297 ↔ 311 By similarity

Sequences

Sequence LengthMass (Da)Tools
Q60823 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 4AB4A9C4FB9CFA7D

FASTA48155,742
        10         20         30         40         50         60 
MNEVSVIKEG WLHKRGEYIK TWRPRYFLLK SDGSFIGYKE RPEAPDQTLP PLNNFSVAEC 

        70         80         90        100        110        120 
QLMKTERPRP NTFVIRCLQW TTVIERTFHV DSPDEREEWM RAIQMVANSL KQRGPGEDAM 

       130        140        150        160        170        180 
DYKCGSPSDS STSEMMEVAV NKARAKVTMN DFDYLKLLGK GTFGKVILVR EKATGRYYAM 

       190        200        210        220        230        240 
KILRKEVIIA KDEVAHTVTE SRVLQNTRHP FLTALKYAFQ THDRLCFVME YANGGELFFH 

       250        260        270        280        290        300 
LSRERVFTED RARFYGAEIV SALEYLHSRD VVYRDIKLEN LMLDKDGHIK ITDFGLCKEG 

       310        320        330        340        350        360 
ISDGATMKTF CGTPEYLAPE VLEDNDYGRA VDWWGLGVVM YEMMCGRLPF YNQDHERLFE 

       370        380        390        400        410        420 
LILMEEIRFP RTLGPEAKSL LAGLLKKDPK QRLGGGPSDA KEVMEHRFFL SINWQDVVQK 

       430        440        450        460        470        480 
KLLPPFKPQV TSEVDTRYFD DEFTAQSITI TPPDRYDSLD PLELDQRTHF PQFSYSASIR 


E 

« Hide

References

« Hide 'large scale' references
[1]"Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene."
Altomare D.A., Guo K., Cheng J.Q., Sonoda G., Walsh K., Testa J.R.
Oncogene 11:1055-1060(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: C57BL/6 X CBA.
Tissue: Thymus.
[2]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Retina and Salivary gland.
[3]"Akt2-mediated phosphorylation of Pitx2 controls Ccnd1 mRNA decay during muscle cell differentiation."
Gherzi R., Trabucchi M., Ponassi M., Gallouzi I.E., Rosenfeld M.G., Briata P.
Cell Death Differ. 17:975-983(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF PTIX2.
[4]"C2 domain-containing phosphoprotein CDP138 regulates GLUT4 insertion into the plasma membrane."
Xie X., Gong Z., Mansuy-Aubert V., Zhou Q.L., Tatulian S.A., Sehrt D., Gnad F., Brill L.M., Motamedchaboki K., Chen Y., Czech M.P., Mann M., Kruger M., Jiang Z.Y.
Cell Metab. 14:378-389(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF C2CD5.
[5]"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.
[6]"Akt1 and Akt2: differentiating the aktion."
Heron-Milhavet L., Khouya N., Fernandez A., Lamb N.J.
Histol. Histopathol. 26:651-662(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U22445 mRNA. Translation: AAA83557.1.
BC026151 mRNA. Translation: AAH26151.1.
BC040377 mRNA. Translation: AAH40377.1.
CCDSCCDS21027.1.
RefSeqNP_001103678.1. NM_001110208.1.
NP_031460.1. NM_007434.3.
XP_006539540.1. XM_006539477.1.
XP_006539541.1. XM_006539478.1.
XP_006539542.1. XM_006539479.1.
XP_006539543.1. XM_006539480.1.
XP_006539544.1. XM_006539481.1.
UniGeneMm.177194.

3D structure databases

ProteinModelPortalQ60823.
SMRQ60823. Positions 1-480.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198057. 2 interactions.
IntActQ60823. 6 interactions.
MINTMINT-1770302.

Chemistry

ChEMBLCHEMBL5382.

PTM databases

PhosphoSiteQ60823.

Proteomic databases

MaxQBQ60823.
PaxDbQ60823.
PRIDEQ60823.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000051356; ENSMUSP00000052103; ENSMUSG00000004056.
ENSMUST00000108343; ENSMUSP00000103980; ENSMUSG00000004056.
ENSMUST00000108344; ENSMUSP00000103981; ENSMUSG00000004056.
ENSMUST00000167435; ENSMUSP00000132141; ENSMUSG00000004056.
GeneID11652.
KEGGmmu:11652.
UCSCuc009fwr.2. mouse.

Organism-specific databases

CTD208.
MGIMGI:104874. Akt2.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00740000114960.
HOGENOMHOG000233033.
HOVERGENHBG108317.
InParanoidQ60823.
KOK04456.
OMAATGMYYA.
OrthoDBEOG7Q5HCW.
PhylomeDBQ60823.
TreeFamTF102004.

Enzyme and pathway databases

BRENDA2.7.11.1. 3474.
ReactomeREACT_13641. Regulation of Beta-Cell Development.
REACT_147847. Translocation of Glut4 to the Plasma Membrane.
REACT_209837. Membrane Trafficking.

Gene expression databases

ArrayExpressQ60823.
BgeeQ60823.
CleanExMM_AKT2.
GenevestigatorQ60823.

Family and domain databases

Gene3D2.30.29.30. 1 hit.
InterProIPR000961. AGC-kinase_C.
IPR011009. Kinase-like_dom.
IPR011993. PH_like_dom.
IPR017892. Pkinase_C.
IPR001849. Pleckstrin_homology.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00169. PH. 1 hit.
PF00069. Pkinase. 1 hit.
PF00433. Pkinase_C. 1 hit.
[Graphical view]
SMARTSM00233. PH. 1 hit.
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS51285. 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]
ProtoNetSearch...

Other

NextBio279261.
PROQ60823.
SOURCESearch...

Entry information

Entry nameAKT2_MOUSE
AccessionPrimary (citable) accession number: Q60823
Entry history
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: November 1, 1996
Last modified: July 9, 2014
This is version 130 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot