P47196 (AKT1_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified May 1, 2013. Version 133. History...
Names and origin
|Protein names||Recommended name:|
RAC-alpha serine/threonine-protein kinase
Protein kinase B
Protein kinase B alpha
Short name=PKB alpha
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||480 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
AKT1 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 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. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation By similarity. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity By similarity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 By similarity. Ref.2 Ref.3 Ref.5 Ref.6
AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation. Ref.2 Ref.3 Ref.5 Ref.6
ATP + a protein = ADP + a phosphoprotein.
Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation.
Interacts (via the C-terminus) with CCDC88A (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE-binding. Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with TNK2 and CLK2. Interacts with RAF1. Interacts (via the C-terminus) with THEM4 (via its C-terminus). Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with and phosphorylated by PDPK1 By similarity.
Cytoplasm By similarity. Nucleus By similarity. Cell membrane By similarity. Note: Nucleus after activation by integrin-linked protein kinase 1 (ILK1). Nuclear translocation is enhanced by interaction with TCL1A By similarity. Phosphorylation on Tyr-176 by TNK2 results in its localization to the cell membrane where it is targeted for further phosphorylations on Thr-308 and Ser-473 leading to its activation and the activated form translocates to the nucleus By similarity.
Widely expressed. Low levels found in liver with slightly higher levels present in thymus and testis.
Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction By similarity.
The AGC-kinase C-terminal mediates interaction with THEM4 By similarity.
O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1. O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site.
Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity. Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA. This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation. Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1. Ser-473 phosphorylation is enhanced by signaling through activated FLT3 By similarity. Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase. The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase By similarity. Ref.3
Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation. When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome. Also ubiquitinated by TRIM13 leading to its proteasomal degradation By similarity. Ref.3
Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition 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 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.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 480||480||RAC-alpha serine/threonine-protein kinase||PRO_0000085607|
|Domain||5 – 108||104||PH|
|Domain||150 – 408||259||Protein kinase|
|Domain||409 – 480||72||AGC-kinase C-terminal|
|Nucleotide binding||156 – 164||9||ATP By similarity|
|Region||14 – 19||6||Inositol-(1,3,4,5)-tetrakisphosphate binding By similarity|
|Region||23 – 25||3||Inositol-(1,3,4,5)-tetrakisphosphate binding By similarity|
|Region||228 – 230||3||Inhibitor binding By similarity|
|Active site||274||1||Proton acceptor By similarity|
|Binding site||53||1||Inositol-(1,3,4,5)-tetrakisphosphate By similarity|
|Binding site||86||1||Inositol-(1,3,4,5)-tetrakisphosphate By similarity|
|Binding site||161||1||Inhibitor; via amide nitrogen By similarity|
|Binding site||230||1||Inhibitor; via amide nitrogen By similarity|
|Binding site||234||1||Inhibitor By similarity|
|Binding site||292||1||Inhibitor By similarity|
Amino acid modifications
|Modified residue||14||1||N6-acetyllysine By similarity|
|Modified residue||20||1||N6-acetyllysine By similarity|
|Modified residue||124||1||Phosphoserine By similarity|
|Modified residue||126||1||Phosphoserine; alternate By similarity|
|Modified residue||129||1||Phosphoserine; alternate By similarity|
|Modified residue||176||1||Phosphotyrosine; by TNK2 By similarity|
|Modified residue||308||1||Phosphothreonine; by PDPK1 By similarity|
|Modified residue||450||1||Phosphothreonine; by MTOR By similarity|
|Modified residue||473||1||Phosphoserine; by MTOR Probable|
|Modified residue||474||1||Phosphotyrosine By similarity|
|Glycosylation||126||1||O-linked (GlcNAc...) By similarity|
|Glycosylation||129||1||O-linked (GlcNAc...) By similarity|
|Glycosylation||305||1||O-linked (GlcNAc...) By similarity|
|Glycosylation||312||1||O-linked (GlcNAc...) By similarity|
|Glycosylation||473||1||O-linked (GlcNAc...); alternate By similarity|
|Disulfide bond||60 ↔ 77||By similarity|
|Disulfide bond||296 ↔ 310||By similarity|
|Mutagenesis||179||1||K → D: Lacks kinase activity. Inhibits insulin-induced activation of glycogen synthase when expressed. Ref.2 Ref.3|
|Mutagenesis||308||1||T → A: Inhibits insulin-induced activation of endogenous Akt1, insulin-stimulated protein synthesis, insulin-induced activation of glycogen synthase and insulin-induced phosphorylation of 4E-BP1 in a dominant negative manner when overexpressed; when associated with A-473. Ref.2 Ref.3|
|Mutagenesis||473||1||S → A: Inhibits insulin-induced activation of endogenous Akt1, insulin-stimulated protein synthesis, insulin-induced activation of glycogen synthase and insulin-induced phosphorylation of 4E-BP1 in a dominant negative manner when overexpressed; when associated with A-308. Ref.2 Ref.3|
|||"Molecular cloning of rat RAC protein kinase alpha and beta and their association with protein kinase C zeta."|
Konishi H., Shinomura T., Kuroda S.I., Ono Y., Kikkawa U.
Biochem. Biophys. Res. Commun. 205:817-825(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"Requirement for activation of the serine-threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but not of glucose transport."|
Kitamura T., Ogawa W., Sakaue H., Hino Y., Kuroda S., Takata M., Matsumoto M., Maeda T., Konishi H., Kikkawa U., Kasuga M.
Mol. Cell. Biol. 18:3708-3717(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, MUTAGENESIS OF LYS-179; THR-308 AND SER-473.
|||"Requirement for Akt (protein kinase B) in insulin-induced activation of glycogen synthase and phosphorylation of 4E-BP1 (PHAS-1)."|
Takata M., Ogawa W., Kitamura T., Hino Y., Kuroda S., Kotani K., Klip A., Gingras A.-C., Sonenberg N., Kasuga M.
J. Biol. Chem. 274:20611-20618(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT THR-308 AND SER-473, MUTAGENESIS OF LYS-179; THR-308 AND SER-473.
|||"The protein kinase B/Akt signalling pathway in human malignancy."|
Nicholson K.M., Anderson N.G.
Cell. Signal. 14:381-395(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
|||"The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes."|
Berwick D.C., Hers I., Heesom K.J., Moule S.K., Tavare J.M.
J. Biol. Chem. 277:33895-33900(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF ACLY.
|||"Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles."|
Berwick D.C., Dell G.C., Welsh G.I., Heesom K.J., Hers I., Fletcher L.M., Cooke F.T., Tavare J.M.
J. Cell Sci. 117:5985-5993(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF PIKFYVE.
|||"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.|
|D30040 mRNA. Translation: BAA06279.1.|
|RefSeq||NP_150233.1. NM_033230.2. |
3D structure databases
|SMR||P47196. Positions 3-121, 144-477. |
Protein-protein interaction databases
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSRNOT00000031164; ENSRNOP00000038369; ENSRNOG00000028629. |
|UCSC||RGD:2081. rat. |
|RGD||2081. Akt1. |
Enzyme and pathway databases
|BRENDA||188.8.131.52. 5301. |
|Reactome||REACT_109781. Immune System. |
REACT_111984. Signal Transduction.
Gene expression databases
|GermOnline||ENSRNOG00000028629. Rattus norvegicus. |
Family and domain databases
|Gene3D||184.108.40.206. 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. 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.
|Accession||Primary (citable) accession number: P47196|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families