Q60823 (AKT2_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 130. History...
Names and origin
|Protein names||Recommended name:|
RAC-beta serine/threonine-protein kinase
Protein kinase Akt-2
Protein kinase B beta
Short name=PKB beta
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||481 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
ATP + a protein = ADP + a phosphoprotein.
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.
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.
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.
Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PIK3CA) results in its targeting to the plasma membrane By similarity.
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.
Contains 1 AGC-kinase C-terminal domain.
Contains 1 PH domain.
Contains 1 protein kinase domain.
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.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 481||481||RAC-beta serine/threonine-protein kinase||PRO_0000085609|
|Domain||5 – 108||104||PH|
|Domain||152 – 409||258||Protein kinase|
|Domain||410 – 481||72||AGC-kinase C-terminal|
|Nucleotide binding||158 – 166||9||ATP By similarity|
|Region||230 – 232||3||Inhibitor binding By similarity|
|Region||277 – 279||3||Inhibitor binding By similarity|
|Region||292 – 293||2||Inhibitor binding By similarity|
|Active site||275||1||Proton acceptor By similarity|
|Binding site||181||1||ATP By similarity|
|Binding site||181||1||Inhibitor By similarity|
|Binding site||200||1||Inhibitor By similarity|
|Binding site||232||1||Inhibitor; via amide nitrogen By similarity|
|Binding site||236||1||Inhibitor By similarity|
|Binding site||279||1||Inhibitor; via carbonyl oxygen[2X39] By similarity|
|Binding site||280||1||Manganese By similarity|
|Binding site||293||1||Inhibitor By similarity|
|Binding site||293||1||Manganese By similarity|
|Binding site||294||1||Inhibitor; via amide nitrogen By similarity|
Amino acid modifications
|Modified residue||1||1||N-acetylmethionine By similarity|
|Modified residue||126||1||Phosphoserine By similarity|
|Modified residue||309||1||Phosphothreonine; by PDPK1 By similarity|
|Modified residue||447||1||Phosphoserine By similarity|
|Modified residue||451||1||Phosphothreonine By similarity|
|Modified residue||474||1||Phosphoserine By similarity|
|Modified residue||478||1||Phosphoserine By similarity|
|Glycosylation||128||1||O-linked (GlcNAc) By similarity|
|Glycosylation||131||1||O-linked (GlcNAc) By similarity|
|Glycosylation||306||1||O-linked (GlcNAc) By similarity|
|Glycosylation||313||1||O-linked (GlcNAc) By similarity|
|Disulfide bond||60 ↔ 77||By similarity|
|Disulfide bond||297 ↔ 311||By similarity|
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.|
|U22445 mRNA. Translation: AAA83557.1.|
BC026151 mRNA. Translation: AAH26151.1.
BC040377 mRNA. Translation: AAH40377.1.
|RefSeq||NP_001103678.1. NM_001110208.1. |
3D structure databases
|SMR||Q60823. Positions 1-480. |
Protein-protein interaction databases
|BioGrid||198057. 2 interactions.|
|IntAct||Q60823. 6 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000051356; ENSMUSP00000052103; ENSMUSG00000004056. |
ENSMUST00000108343; ENSMUSP00000103980; ENSMUSG00000004056.
ENSMUST00000108344; ENSMUSP00000103981; ENSMUSG00000004056.
ENSMUST00000167435; ENSMUSP00000132141; ENSMUSG00000004056.
|UCSC||uc009fwr.2. mouse. |
|MGI||MGI:104874. Akt2. |
Enzyme and pathway databases
|BRENDA||18.104.22.168. 3474. |
|Reactome||REACT_13641. Regulation of Beta-Cell Development. |
REACT_147847. Translocation of Glut4 to the Plasma Membrane.
REACT_209837. Membrane Trafficking.
Gene expression databases
Family and domain databases
|Gene3D||22.214.171.124. 1 hit. |
|InterPro||IPR000961. AGC-kinase_C. |
|Pfam||PF00169. PH. 1 hit. |
PF00069. Pkinase. 1 hit.
PF00433. Pkinase_C. 1 hit.
|SMART||SM00233. PH. 1 hit. |
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
|SUPFAM||SSF56112. SSF56112. 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.
|Accession||Primary (citable) accession number: Q60823|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|