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Protein

RAC-alpha serine/threonine-protein kinase

Gene

Akt1

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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).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.4 Publications

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

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.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei53Inositol-(1,3,4,5)-tetrakisphosphateBy similarity1
Binding sitei86Inositol-(1,3,4,5)-tetrakisphosphateBy similarity1
Binding sitei161Inhibitor; via amide nitrogenBy similarity1
Binding sitei179ATP1
Binding sitei230Inhibitor; via amide nitrogenBy similarity1
Binding sitei234InhibitorBy similarity1
Active sitei274Proton acceptorPROSITE-ProRule annotation1
Binding sitei292InhibitorBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi156 – 164ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • 14-3-3 protein binding Source: Ensembl
  • ATP binding Source: RGD
  • enzyme binding Source: BHF-UCL
  • GTPase activating protein binding Source: RGD
  • nitric-oxide synthase regulator activity Source: Ensembl
  • phosphatidylinositol-3,4,5-trisphosphate binding Source: Ensembl
  • phosphatidylinositol-3,4-bisphosphate binding Source: Ensembl
  • protein homodimerization activity Source: Ensembl
  • protein kinase activity Source: RGD
  • protein kinase binding Source: RGD
  • protein kinase C binding Source: RGD
  • protein phosphatase 2A binding Source: RGD
  • protein serine/threonine/tyrosine kinase activity Source: Ensembl
  • protein serine/threonine kinase activity Source: BHF-UCL

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein, Kinase, Serine/threonine-protein kinase, Transferase
Biological processApoptosis, Carbohydrate metabolism, Glucose metabolism, Glycogen biosynthesis, Glycogen metabolism, Neurogenesis, Sugar transport, Translation regulation, Transport
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.1 5301
ReactomeiR-RNO-1257604 PIP3 activates AKT signaling
R-RNO-1358803 Downregulation of ERBB2:ERBB3 signaling
R-RNO-1474151 Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
R-RNO-165159 mTOR signalling
R-RNO-198323 AKT phosphorylates targets in the cytosol
R-RNO-198693 AKT phosphorylates targets in the nucleus
R-RNO-199418 Negative regulation of the PI3K/AKT network
R-RNO-203615 eNOS activation
R-RNO-211163 AKT-mediated inactivation of FOXO1A
R-RNO-354192 Integrin alphaIIb beta3 signaling
R-RNO-3769402 Deactivation of the beta-catenin transactivating complex
R-RNO-389357 CD28 dependent PI3K/Akt signaling
R-RNO-389513 CTLA4 inhibitory signaling
R-RNO-392451 G beta:gamma signalling through PI3Kgamma
R-RNO-450385 Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
R-RNO-450604 KSRP (KHSRP) binds and destabilizes mRNA
R-RNO-5218920 VEGFR2 mediated vascular permeability
R-RNO-5628897 TP53 Regulates Metabolic Genes
R-RNO-6804757 Regulation of TP53 Degradation
R-RNO-6804758 Regulation of TP53 Activity through Acetylation
R-RNO-6804759 Regulation of TP53 Activity through Association with Co-factors
R-RNO-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-RNO-69202 Cyclin E associated events during G1/S transition
R-RNO-69656 Cyclin A:Cdk2-associated events at S phase entry
R-RNO-8849469 PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1
R-RNO-8876198 RAB GEFs exchange GTP for GDP on RABs
R-RNO-8948751 Regulation of PTEN stability and activity

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:Akt1
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 6

Organism-specific databases

RGDi2081 Akt1

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, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi179K → D: Lacks kinase activity. Inhibits insulin-induced activation of glycogen synthase when expressed. 2 Publications1
Mutagenesisi308T → 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. 2 Publications1
Mutagenesisi473S → 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. 2 Publications1

Chemistry databases

ChEMBLiCHEMBL1075215

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000856071 – 480RAC-alpha serine/threonine-protein kinaseAdd BLAST480

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei14N6-acetyllysineBy similarity1
Modified residuei20N6-acetyllysineBy similarity1
Disulfide bondi60 ↔ 77By similarity
Modified residuei124PhosphoserineCombined sources1
Modified residuei126Phosphoserine; alternateBy similarity1
Glycosylationi126O-linked (GlcNAc) serine; alternateBy similarity1
Modified residuei129Phosphoserine; alternateCombined sources1
Glycosylationi129O-linked (GlcNAc) serine; alternateBy similarity1
Modified residuei176Phosphotyrosine; by TNK2By similarity1
Cross-linki284Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Disulfide bondi296 ↔ 310By similarity
Glycosylationi305O-linked (GlcNAc) threonineBy similarity1
Modified residuei308Phosphothreonine; by IKKE, PDPK1 and TBK1By similarity1
Glycosylationi312O-linked (GlcNAc) threonineBy similarity1
Modified residuei448PhosphothreonineBy similarity1
Modified residuei450Phosphothreonine; by MTORBy similarity1
Modified residuei473Phosphoserine; by IKKE, MTOR and TBK1; alternate1 Publication1
Glycosylationi473O-linked (GlcNAc) serine; alternate1
Modified residuei474PhosphotyrosineBy similarity1

Post-translational modificationi

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.1 Publication
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. Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (By similarity). 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. Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (By similarity).By similarity
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. Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation (By similarity).By similarity
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).By similarity

Keywords - PTMi

Acetylation, Disulfide bond, Glycoprotein, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP47196
PRIDEiP47196

PTM databases

iPTMnetiP47196
PhosphoSitePlusiP47196

Expressioni

Tissue specificityi

Widely expressed. Low levels found in liver with slightly higher levels present in thymus and testis.

Gene expression databases

BgeeiENSRNOG00000028629
GenevisibleiP47196 RN

Interactioni

Subunit structurei

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). Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts with PA2G4. Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (By similarity). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (By similarity). Interacts with WDFY2 (via WD repeats 1-3) (By similarity). Forms a complex with WDFY2 and FOXO1 (By similarity). Interacts with FAM168A (By similarity). Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (By similarity). Interacts with PKHM3 (By similarity).By similarity1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • 14-3-3 protein binding Source: Ensembl
  • enzyme binding Source: BHF-UCL
  • GTPase activating protein binding Source: RGD
  • protein homodimerization activity Source: Ensembl
  • protein kinase binding Source: RGD
  • protein kinase C binding Source: RGD
  • protein phosphatase 2A binding Source: RGD

Protein-protein interaction databases

BioGridi246375, 13 interactors
DIPiDIP-42185N
IntActiP47196, 12 interactors
MINTiP47196
STRINGi10116.ENSRNOP00000038369

Structurei

3D structure databases

ProteinModelPortaliP47196
SMRiP47196
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini5 – 108PHPROSITE-ProRule annotationAdd BLAST104
Domaini150 – 408Protein kinasePROSITE-ProRule annotationAdd BLAST259
Domaini409 – 480AGC-kinase C-terminalAdd BLAST72

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni14 – 19Inositol-(1,3,4,5)-tetrakisphosphate bindingBy similarity6
Regioni23 – 25Inositol-(1,3,4,5)-tetrakisphosphate bindingBy similarity3
Regioni228 – 230Inhibitor bindingBy similarity3

Domaini

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).By similarity
The AGC-kinase C-terminal mediates interaction with THEM4.By similarity

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0598 Eukaryota
ENOG410XNPH LUCA
GeneTreeiENSGT00920000148938
HOGENOMiHOG000233033
HOVERGENiHBG108317
InParanoidiP47196
KOiK04456
OMAiQHRFFAS
OrthoDBiEOG091G06FF
PhylomeDBiP47196
TreeFamiTF102004

Family and domain databases

CDDicd01241 PH_PKB, 1 hit
cd05594 STKc_PKB_alpha, 1 hit
Gene3Di2.30.29.30, 1 hit
InterProiView protein in InterPro
IPR000961 AGC-kinase_C
IPR034676 Akt1
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.

P47196-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MNDVAIVKEG WLHKRGEYIK TWRPRYFLLK NDGTFIGYKE RPQDVEQRES
60 70 80 90 100
PLNNFSVAQC QLMKTERPRP NTFIIRCLQW TTVIERTFHV ETPEEREEWT
110 120 130 140 150
TAIQTVADGL KRQEEETMDF RSGSPSDNSG AEEMEVALAK PKHRVTMNEF
160 170 180 190 200
EYLKLLGKGT FGKVILVKEK ATGRYYAMKI LKKEVIVAKD EVAHTLTENR
210 220 230 240 250
VLQNSRHPFL TALKYSFQTH DRLCFVMEYA NGGELFFHLS RERVFSEDRA
260 270 280 290 300
RFYGAEIVSA LDYLHSEKNV VYRDLKLENL MLDKDGHIKI TDFGLCKEGI
310 320 330 340 350
KDGATMKTFC GTPEYLAPEV LEDNDYGRAV DWWGLGVVMY EMMCGRLPFY
360 370 380 390 400
NQDHEKLFEL ILMEEIRFPR TLGPEAKSLL SGLLKKDPTQ RLGGGSEDAK
410 420 430 440 450
EIMQHRFFAN IVWQDVYEKK LSPPFKPQVT SETDTRYFDE EFTAQMITIT
460 470 480
PPDQDDSMEC VDSERRPHFP QFSYSASGTA
Length:480
Mass (Da):55,735
Last modified:February 1, 1996 - v1
Checksum:i5DCAAE7134366D04
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D30040 mRNA Translation: BAA06279.1
PIRiJC2437
RefSeqiNP_150233.1, NM_033230.2
XP_006240693.1, XM_006240631.2
UniGeneiRn.11422

Genome annotation databases

EnsembliENSRNOT00000031164; ENSRNOP00000038369; ENSRNOG00000028629
GeneIDi24185
KEGGirno:24185
UCSCiRGD:2081 rat

Similar proteinsi

Entry informationi

Entry nameiAKT1_RAT
AccessioniPrimary (citable) accession number: P47196
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: July 18, 2018
This is version 189 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. SIMILARITY comments
    Index of protein domains and families

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