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UniProtKB - Q60823 (AKT2_MOUSE)

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Protein

RAC-beta serine/threonine-protein kinase

Gene

Akt2

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

Functioni

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 specificity has 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 of cyclic 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.
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 responsible of 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'.

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-309) and the other in the C-terminal regulatory region (Ser-474), need to be phosphorylated for its full activation.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei181ATPPROSITE-ProRule annotation1
Binding sitei181InhibitorBy similarity1
Binding sitei200InhibitorBy similarity1
Binding sitei232Inhibitor; via amide nitrogenBy similarity1
Binding sitei236InhibitorBy similarity1
Active sitei275Proton acceptorPROSITE-ProRule annotation1
Binding sitei279Inhibitor; via carbonyl oxygenBy similarity1
Metal bindingi280ManganeseBy similarity1
Metal bindingi293ManganeseBy similarity1
Binding sitei293InhibitorBy similarity1
Binding sitei294Inhibitor; via amide nitrogenBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi158 – 166ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: MGI
  • metal ion binding Source: UniProtKB-KW
  • protein kinase activity Source: MGI
  • protein kinase C binding Source: MGI
  • protein serine/threonine kinase activity Source: MGI
View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionDevelopmental protein, Kinase, Serine/threonine-protein kinase, Transferase
Biological processApoptosis, Carbohydrate metabolism, Glucose metabolism, Glycogen biosynthesis, Glycogen metabolism, Sugar transport, Translation regulation, Transport
LigandATP-binding, Manganese, Metal-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-165158 Activation of AKT2
R-MMU-165181 Inhibition of TSC complex formation by PKB
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-3769402 Deactivation of the beta-catenin transactivating complex
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-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 namesi
Name:Akt2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus
Proteomesi
  • UP000000589 Componenti: Chromosome 7

Organism-specific databases

MGIiMGI:104874 Akt2

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

Cell membrane, Cytoplasm, Endosome, Membrane, Nucleus

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL5382

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000856091 – 481RAC-beta serine/threonine-protein kinaseAdd BLAST481

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineBy similarity1
Modified residuei34PhosphoserineBy similarity1
Disulfide bondi60 ↔ 77By similarity
Modified residuei126PhosphoserineCombined sources1
Glycosylationi128O-linked (GlcNAc) serineBy similarity1
Glycosylationi131O-linked (GlcNAc) serineBy similarity1
Disulfide bondi297 ↔ 311By similarity
Glycosylationi306O-linked (GlcNAc) threonineBy similarity1
Modified residuei309Phosphothreonine; by PDPK1By similarity1
Glycosylationi313O-linked (GlcNAc) threonineBy similarity1
Modified residuei447PhosphoserineBy similarity1
Modified residuei451PhosphothreonineCombined sources1
Modified residuei474PhosphoserineBy similarity1
Modified residuei478PhosphoserineBy similarity1

Post-translational modificationi

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).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

Keywords - PTMi

Acetylation, Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ60823
MaxQBiQ60823
PaxDbiQ60823
PRIDEiQ60823

PTM databases

iPTMnetiQ60823
PhosphoSitePlusiQ60823

Expressioni

Gene expression databases

BgeeiENSMUSG00000004056
CleanExiMM_AKT2
ExpressionAtlasiQ60823 baseline and differential
GenevisibleiQ60823 MM

Interactioni

Subunit structurei

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). Interacts with BTBD10 (PubMed:18160256). Interacts with KCTD20 (PubMed:24156551). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529, PubMed:20189988).By similarity4 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi198057, 10 interactors
IntActiQ60823, 28 interactors
STRINGi10090.ENSMUSP00000052103

Structurei

3D structure databases

ProteinModelPortaliQ60823
SMRiQ60823
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini5 – 108PHPROSITE-ProRule annotationAdd BLAST104
Domaini152 – 409Protein kinasePROSITE-ProRule annotationAdd BLAST258
Domaini410 – 481AGC-kinase C-terminalAdd BLAST72

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni230 – 232Inhibitor bindingBy similarity3
Regioni277 – 279Inhibitor bindingBy similarity3
Regioni292 – 293Inhibitor bindingBy similarity2

Domaini

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

Sequence similaritiesi

Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.Curated

Phylogenomic databases

eggNOGiKOG0598 Eukaryota
ENOG410XNPH LUCA
GeneTreeiENSGT00920000148938
HOGENOMiHOG000233033
HOVERGENiHBG108317
InParanoidiQ60823
KOiK04456
OMAiEPMEIKF
OrthoDBiEOG091G06FF
PhylomeDBiQ60823
TreeFamiTF102004

Family and domain databases

CDDicd01241 PH_PKB, 1 hit
cd05595 STKc_PKB_beta, 1 hit
Gene3Di2.30.29.30, 1 hit
InterProiView protein in InterPro
IPR000961 AGC-kinase_C
IPR034677 Akt2
IPR011009 Kinase-like_dom_sf
IPR011993 PH-like_dom_sf
IPR001849 PH_domain
IPR039026 PH_PKB
IPR017892 Pkinase_C
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR039027 RAC_alpha/beta
IPR008271 Ser/Thr_kinase_AS
PANTHERiPTHR24356:SF176 PTHR24356:SF176, 1 hit
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

Sequencei

Sequence statusi: Complete.

Q60823-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MNEVSVIKEG WLHKRGEYIK TWRPRYFLLK SDGSFIGYKE RPEAPDQTLP 
        60         70         80         90        100
PLNNFSVAEC QLMKTERPRP NTFVIRCLQW TTVIERTFHV DSPDEREEWM 
       110        120        130        140        150
RAIQMVANSL KQRGPGEDAM DYKCGSPSDS STSEMMEVAV NKARAKVTMN 
       160        170        180        190        200
DFDYLKLLGK GTFGKVILVR EKATGRYYAM KILRKEVIIA KDEVAHTVTE 
       210        220        230        240        250
SRVLQNTRHP FLTALKYAFQ THDRLCFVME YANGGELFFH LSRERVFTED 
       260        270        280        290        300
RARFYGAEIV SALEYLHSRD VVYRDIKLEN LMLDKDGHIK ITDFGLCKEG 
       310        320        330        340        350
ISDGATMKTF CGTPEYLAPE VLEDNDYGRA VDWWGLGVVM YEMMCGRLPF 
       360        370        380        390        400
YNQDHERLFE LILMEEIRFP RTLGPEAKSL LAGLLKKDPK QRLGGGPSDA 
       410        420        430        440        450
KEVMEHRFFL SINWQDVVQK KLLPPFKPQV TSEVDTRYFD DEFTAQSITI 
       460        470        480 
TPPDRYDSLD PLELDQRTHF PQFSYSASIR E
Length:481
Mass (Da):55,742
Last modified:November 1, 1996 - v1
Checksum:i4AB4A9C4FB9CFA7D
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U22445 mRNA Translation: AAA83557.1
BC026151 mRNA Translation: AAH26151.1
BC040377 mRNA Translation: AAH40377.1
CCDSiCCDS21027.1
RefSeqiNP_001103678.1, NM_001110208.2
NP_001318037.1, NM_001331108.1
NP_001318038.1, NM_001331109.1
NP_031460.1, NM_007434.4
XP_006539540.1, XM_006539477.1
XP_006539543.1, XM_006539480.1
XP_006539544.1, XM_006539481.3
UniGeneiMm.177194

Genome annotation databases

EnsembliENSMUST00000051356; ENSMUSP00000052103; ENSMUSG00000004056
ENSMUST00000108343; ENSMUSP00000103980; ENSMUSG00000004056
ENSMUST00000108344; ENSMUSP00000103981; ENSMUSG00000004056
ENSMUST00000167435; ENSMUSP00000132141; ENSMUSG00000004056
GeneIDi11652
KEGGimmu:11652
UCSCiuc009fwr.2 mouse

Similar proteinsi

Entry informationi

Entry nameiAKT2_MOUSE
AccessioniPrimary (citable) accession number: Q60823
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: November 1, 1996
Last modified: July 18, 2018
This is version 171 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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