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Q01314 (AKT1_BOVIN) Reviewed, UniProtKB/Swiss-Prot

Last modified May 1, 2013. Version 125. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

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

EC=2.7.11.1
Alternative name(s):
Protein kinase B
Short name=PKB
Protein kinase B alpha
Short name=PKB alpha
RAC-PK-alpha
Gene names
Name:AKT1
Synonyms:PKB
OrganismBos taurus (Bovine) [Reference proteome]
Taxonomic identifier9913 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos

Protein attributes

Sequence length480 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. nuclear translocation. 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.

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. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation By similarity.

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Subunit structure

Interacts (via the C-terminus) with CCDC88A (via its C-terminus) and THEM4 (via its C-terminus). Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with TRAF6. Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE binding. Interacts with RARA; the interaction phosphorylates RARA and represses its transactivation activity. Interacts with MAP3K5 and TNK2. Interacts with BAD, CLK2, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with RAF1. Interacts with PKN2 (via C-terminal domain); the interaction occurs with the C-terminus cleavage products of PKN2 in apoptotic cells. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with and phosphorylated by PDPK1 By similarity.

Subcellular location

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.

Domain

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.

Post-translational modification

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 By similarity.

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. Ser-473 is dephosphorylated by PHLPP. 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.4

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.4

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.

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 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.

Ontologies

Keywords
   Biological processApoptosis
Carbohydrate metabolism
Glucose metabolism
Glycogen biosynthesis
Glycogen metabolism
Neurogenesis
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_processcarbohydrate transport

Inferred from electronic annotation. Source: UniProtKB-KW

glucose metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

glycogen biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of cysteine-type endopeptidase activity involved in apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of release of cytochrome c from mitochondria

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of cell migration

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of neuron projection development

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of translation

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

plasma membrane

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

phospholipid binding

Inferred from electronic annotation. Source: InterPro

protein serine/threonine kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

PplQ9R2692EBI-368344,EBI-368293From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 480480RAC-alpha serine/threonine-protein kinase
PRO_0000085604

Regions

Domain5 – 108104PH
Domain150 – 408259Protein kinase
Domain409 – 48072AGC-kinase C-terminal
Nucleotide binding156 – 1649ATP By similarity
Region14 – 196Inositol-(1,3,4,5)-tetrakisphosphate binding By similarity
Region23 – 253Inositol-(1,3,4,5)-tetrakisphosphate binding By similarity
Region228 – 2303Inhibitor binding By similarity

Sites

Active site2741Proton acceptor By similarity
Binding site531Inositol-(1,3,4,5)-tetrakisphosphate By similarity
Binding site861Inositol-(1,3,4,5)-tetrakisphosphate By similarity
Binding site1611Inhibitor; via amide nitrogen By similarity
Binding site1791ATP By similarity
Binding site2301Inhibitor; via amide nitrogen By similarity
Binding site2341Inhibitor By similarity
Binding site2921Inhibitor By similarity

Amino acid modifications

Modified residue141N6-acetyllysine By similarity
Modified residue201N6-acetyllysine By similarity
Modified residue1241Phosphoserine By similarity
Modified residue1291Phosphoserine; alternate By similarity
Modified residue1761Phosphotyrosine; by TNK2 By similarity
Modified residue3081Phosphothreonine; by PDPK1 By similarity
Modified residue4501Phosphothreonine; by MTOR By similarity
Modified residue4731Phosphoserine; by MTOR Probable
Modified residue4741Phosphotyrosine By similarity
Glycosylation1291O-linked (GlcNAc...) By similarity
Glycosylation3051O-linked (GlcNAc...) By similarity
Glycosylation3121O-linked (GlcNAc...) By similarity
Glycosylation4731O-linked (GlcNAc...); alternate By similarity
Disulfide bond60 ↔ 77 By similarity
Disulfide bond296 ↔ 310 By similarity

Experimental info

Sequence conflict1491D → E in CAA43371. Ref.1
Sequence conflict1531L → V in CAA43371. Ref.1
Sequence conflict173 – 1742GR → AA in CAA43371. Ref.1
Sequence conflict2091F → S in CAA43371. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q01314 [UniParc].

Last modified July 25, 2006. Version 2.
Checksum: 152E6613C4E6ED5A

FASTA48055,748
        10         20         30         40         50         60 
MNDVAIVKEG WLHKRGEYIK TWRPRYFLLK NDGTFIGYKE RPQDLEQRES PLNNFSVAQC 

        70         80         90        100        110        120 
QLMKTERPRP NTFIIRCLQW TTVIERTFHV ETPEEREEWT TAIQTVADGL KRQEEETMDF 

       130        140        150        160        170        180 
RSGSPGENSG AEEMEVSLAK PKHRVTMNDF EYLKLLGKGT FGKVILVKEK ATGRYYAMKI 

       190        200        210        220        230        240 
LKKEVIVAKD EVAHTLTENR VLQNSRHPFL TALKYSFQTH DRLCFVMEYA NGGELFFHLS 

       250        260        270        280        290        300 
RERVFSEDRA RFYGAEIVSA LDYLHSEKEV VYRDLKLENL MLDKDGHIKI TDFGLCKEGI 

       310        320        330        340        350        360 
KDGATMKTFC GTPEYLAPEV LEDNDYGRAV DWWGLGVVMY EMMCGRLPFY NQDHEKLFEL 

       370        380        390        400        410        420 
ILMEEIRFPR TLSPEAKSLL SGLLKKDPKQ RLGGGSEDAK EIMQHRFFAS IVWQDVYEKK 

       430        440        450        460        470        480 
LSPPFKPQVT SETDTRYFDE EFTAQMITIT PPDQDDSMEG VDSERRPHFP QFSYSASATA 

« Hide

References

[1]"Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families."
Coffer P.J., Woodgett J.R.
Eur. J. Biochem. 201:475-481(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Brain.
[2]Erratum
Coffer P.J., Woodgett J.R.
Eur. J. Biochem. 205:1217-1218(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: SEQUENCE REVISION.
[3]"Complete sequence of the bovine AKT1 gene."
Khatib H.
Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Brain.
[4]"PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth."
Gao T., Furnari F., Newton A.C.
Mol. Cell 18:13-24(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: DEPHOSPHORYLATION AT SER-473 BY PHLPP.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X61036 mRNA. Translation: CAA43371.1.
AY781100 mRNA. Translation: AAW71957.1.
IPIIPI00696205.
PIRS62117.
RefSeqNP_776411.1. NM_173986.2.
UniGeneBt.4843.

3D structure databases

ProteinModelPortalQ01314.
SMRQ01314. Positions 3-121, 144-478.
ModBaseSearch...

Protein-protein interaction databases

IntActQ01314. 1 interaction.
STRING9913.ENSBTAP00000051717.

Proteomic databases

PRIDEQ01314.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID280991.
KEGGbta:280991.

Organism-specific databases

CTD207.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233033.
HOVERGENHBG108317.
KOK04456.

Enzyme and pathway databases

BRENDA2.7.11.1. 908.

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_cat_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. Kinase_like. 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

ChEMBLCHEMBL1250377.
NextBio20805091.

Entry information

Entry nameAKT1_BOVIN
AccessionPrimary (citable) accession number: Q01314
Secondary accession number(s): Q5ER96
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: July 25, 2006
Last modified: May 1, 2013
This is version 125 of the entry and version 2 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