AKT2 - RAC-beta serine/threonine-protein kinase - human protein (Function)
 
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AKT2 »  RAC-beta serine/threonine-protein kinase
 
Gene name:  AKT2
Entry whose protein(s) existence is based on evidence at protein level
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Function

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Overview 
AKT2 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. 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 PI(3)P-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 (PI(3)K) 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.  
2
  • CuratedUniProtKB
One of the few specific substrates of AKT2 identified recently 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. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr-343'.  
2
  • CuratedUniProtKB
GO molecular function 
ATP bindingdefinition[GO:0005524]  
1
  • IDAUniProtKB
Protein bindingdefinition[GO:0005515]  
10
  • IPIUniProtKB
  • IPIIntAct
  • IPIHGNC
Protein serine/threonine kinase activitydefinition[GO:0004674]  
2
  • TASUniProtKB
GO biological process 
Activation of Ral GTPase activitydefinition[GO:0032859] silver  
  • IEAOrtholog Compara
Apoptotic processdefinition[GO:0006915]  
  • IEAUniProtKB KW
Carbohydrate transportdefinition[GO:0008643]  
  • IEAUniProtKB KW
Cellular protein modification processdefinition[GO:0006464]  
1
  • TASPINC
Cellular response to insulin stimulusdefinition[GO:0032869]  
1
  • IMPBHF-UCL
Fat cell differentiationdefinition[GO:0045444]  
1
  • TASUniProtKB
Glucose metabolic processdefinition[GO:0006006]  
  • IEAUniProtKB KW
Glycogen biosynthetic processdefinition[GO:0005978]  
  • IEAUniProtKB KW
Insulin receptor signaling pathwaydefinition[GO:0008286]  
2
  • TASUniProtKB
  • IMPBHF-UCL
Intracellular protein transmembrane transportdefinition[GO:0065002]  
  • ISSOrtholog Curator
Mammary gland epithelial cell differentiationdefinition[GO:0060644]  
1
  • TASUniProtKB
Negative regulation of plasma membrane long-chain fatty acid transportdefinition[GO:0010748]  
1
  • IMPBHF-UCL
Peripheral nervous system myelin maintenancedefinition[GO:0032287] silver  
  • IEAOrtholog Compara
Positive regulation of cell motilitydefinition[GO:2000147]  
1
  • IMPBHF-UCL
Positive regulation of fatty acid beta-oxidationdefinition[GO:0032000]  
1
  • IMPBHF-UCL
Positive regulation of glucose importdefinition[GO:0046326]  
1
  • IMPBHF-UCL
Positive regulation of glucose import in response to insulin stimulusdefinition[GO:2001275] silver  
  • IEAOrtholog Compara
Positive regulation of glucose metabolic processdefinition[GO:0010907]  
1
  • IMPBHF-UCL
Positive regulation of glycogen biosynthetic processdefinition[GO:0045725]  
1
  • IMPBHF-UCL
Positive regulation of protein phosphorylationdefinition[GO:0001934]  
  • ISSOrtholog Curator
Positive regulation of protein targeting to membranedefinition[GO:0090314]  
  • ISSOrtholog Curator
Positive regulation of vesicle fusiondefinition[GO:0031340]  
  • ISSOrtholog Curator
Protein localization to plasma membranedefinition[GO:0072659] silver  
  • IEAOrtholog Compara
Protein phosphorylationdefinition[GO:0006468] silver  
  • IEAOrtholog Compara
Regulation of cell cycle arrestdefinition[GO:0071156]  
1
  • TASUniProtKB
Regulation of cell migrationdefinition[GO:0030334]  
1
  • TASUniProtKB
Regulation of translationdefinition[GO:0006417]  
  • IEAUniProtKB KW
Signal transductiondefinition[GO:0007165]  
1
  • TASUniProtKB
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC 2.7.11.1: ATP + a protein ADP + a phosphoprotein.  
  • CuratedUniProtKB
It is regulated in the following manner
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. Aminofurazans are potent AKT2 inhibitors.  
2
  • CuratedUniProtKB
 
More information is available from:
Pathways 
According to KEGG, this protein belongs to the following pathways:
Acute myeloid leukemia  hsa05221+208  
Adipocytokine signaling pathway  hsa04920+208  
Apoptosis  hsa04210+208  
B cell receptor signaling pathway  hsa04662+208  
Carbohydrate digestion and absorption  hsa04973+208  
Chagas disease (American trypanosomiasis)  hsa05142+208  
Chemokine signaling pathway  hsa04062+208  
Cholinergic synapse  hsa04725+208  
Chronic myeloid leukemia  hsa05220+208  
Colorectal cancer  hsa05210+208  
Dopaminergic synapse  hsa04728+208  
Endometrial cancer  hsa05213+208  
ErbB signaling pathway  hsa04012+208  
Fc epsilon RI signaling pathway  hsa04664+208  
Fc gamma R-mediated phagocytosis  hsa04666+208  
Focal adhesion  hsa04510+208  
Glioma  hsa05214+208  
Hepatitis C  hsa05160+208  
HTLV-I infection  hsa05166+208  
Influenza A  hsa05164+208  
Insulin signaling pathway  hsa04910+208  
Jak-STAT signaling pathway  hsa04630+208  
MAPK signaling pathway  hsa04010+208  
Measles  hsa05162+208  
Melanoma  hsa05218+208  
mTOR signaling pathway  hsa04150+208  
Neurotrophin signaling pathway  hsa04722+208  
Non-small cell lung cancer  hsa05223+208  
Osteoclast differentiation  hsa04380+208  
Pancreatic cancer  hsa05212+208  
Pathways in cancer  hsa05200+208  
Progesterone-mediated oocyte maturation  hsa04914+208  
Prostate cancer  hsa05215+208  
Renal cell carcinoma  hsa05211+208  
Small cell lung cancer  hsa05222+208  
T cell receptor signaling pathway  hsa04660+208  
Tight junction  hsa04530+208  
Toll-like receptor signaling pathway  hsa04620+208  
Toxoplasmosis  hsa05145+208  
Tuberculosis  hsa05152+208  
VEGF signaling pathway  hsa04370+208  
According to Reactome, this protein belongs to the following pathways:
Activation of PKB  REACT_790  
AKT phosphorylates targets in the cytosol  REACT_12564  
AKT phosphorylates targets in the nucleus  REACT_12442  
AKT-mediated inactivation of FOXO1A  REACT_13655  
CD28 dependent PI3K/Akt signaling  REACT_19358  
Constitutive PI3K/AKT Signaling in Cancer  REACT_147727  
CTLA4 inhibitory signaling  REACT_19405  
deactivation of the beta-catenin transactivating complex  REACT_200731  
Downregulation of ERBB2:ERBB3 signaling  REACT_115662  
G beta:gamma signalling through PI3Kgamma  REACT_19290  
GPVI-mediated activation cascade  REACT_1695  
Inhibition of TSC complex formation by PKB  REACT_6743  
Negative regulation of the PI3K/AKT network  REACT_12447  
PDE3B signalling  REACT_1451  
PIP3 activates AKT signaling  REACT_75829  
Translocation of GLUT4 to the plasma membrane  REACT_147867  
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.  
  • CuratedUniProtKB
 

Biophysicochemical properties

Kinetic parameters
KM 564 uM for ATP (for recombinant myristoylated AKT2 expressed and immunoprecipitated from Rat-1 cells)
KM 2.3 uM for peptide substrate (for recombinant myristoylated AKT2 expressed and immunoprecipitated from Rat-1 cells)
KM 358.4 uM for ATP (for purified and in vitro activated AKT2)
KM 3.4 uM for peptide substrate (for purified and in vitro activated AKT2)

Keywords

Biological process 
Apoptosis  definition   [KW-0053]
Carbohydrate metabolism  definition   [KW-0119]
Glucose metabolism  definition   [KW-0313]
Glycogen biosynthesis  definition   [KW-0320]
Glycogen metabolism  definition   [KW-0321]
Sugar transport  definition   [KW-0762]
Translation regulation  definition   [KW-0810]
Transport  definition   [KW-0813]
Molecular function 
Developmental protein  definition   [KW-0217]
Kinase  definition   [KW-0418]
Serine/threonine-protein kinase  definition   [KW-0723]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: AKT2
GenomeRNAi: 208
PRO: PR:P31751
Chemistry
GuidetoPHARMACOLOGY: 1480