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AKT3 (v-akt murine thymoma viral oncogene homolog 3, Protein Kinase B gamma)

Identity

Other namesDKFZP434N0250
PKBG
PRKBG
RAC-PK-gamma
HGNC (Hugo) AKT3
LocusID (NCBI) 10000
Location 1q43
Location_base_pair Starts at 243663021 and ends at 244006886 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note Location in the mouse: chromosome 1 in band H4-H6

DNA/RNA

Description The AKT3 gene is composed of 14 exons spanning a genomic region of 354,937 bp.
Transcription AKT3 coding sequence consists of 1,440 bp from the start codon to the stop codon.

Protein

 
  Diagram of the AKT3 protein in scale. The numbers represent specific residues. The domains are PH (Pleckstrin Homology), a short helical region, Kinase (Catalytic Kinase), and Regulatory (Regulatory Region). Indicated are the two phosphorylation sites shown to be essential for activation of AKT3: Threonine 305 and serine 472. C: Carboxyl-terminal; N: Amino-terminal.
Description The AKT3 serine/threonine kinase consists of 479 amino acids with a calculated molecular weight of 55.8 kDa (approximate molecular weight of 59-60 kDa seen on a Western blot). The protein contains three important regions: the PH domain at the N terminus (residues 1-107), a kinase domain (residues 148-405), and a C-terminal regulatory domain (residues 406-479). A 465-amino acid splice variant lacking the serine 472 residue has been identified, which results from alternative splicing of an exon at the C terminus.
Expression Northern blot analysis of AKT3 indicated that it is expressed in virtually all tissues, predominantly in the brain and fetal heart and at lower levels in liver and skeletal muscle. RT-PCR analysis also indicated expression of AKT3 in a wide variety of tissues.
Localisation Predominantly cytoplasmic; also found at the plasma membrane and in the nucleus following its activation.
Function AKT family members are serine/threonine kinases activated following stimulation by growth factors, hormones and the extracellular matrix. AKT kinases play a key role in proliferation, cell survival, and tumorigenesis. Binding of ligands (e.g., EGF) to tyrosine kinase receptors or G-protein coupled receptors leads to the recruitment and activation of the Class 1A and Class 1B PI3K (Phosphatidylinositol 3-Kinase), respectively. The pleckstrin homology domain of AKT kinases has affinity for the 3'-phosphorylated phosphoinositides 3,4,5-trisphosphate (PI-3,4,5-P3) and PI-3,4-P2 produced by PI3K, and they are activated specifically by the latter lipid. Phospholipid binding triggers the translocation of AKT kinases to the plasma membrane. There, AKT is activated through phosphorylation of a threonine (T308 in AKT1, T309 in AKT2 and T305 in AKT3) by PDK1 and on a serine (S473 on AKT1, S474 on AKT2, and S472 on AKT3) by PDK2. Activated AKT then phosphorylates a number of different substrates involved in survival, cell cycle progression, and other pathways implicated in tumorigenesis.
Homology AKT3 is a serine/threonine kinase and is a member of the AKT family that also includes AKT1 and AKT2. At the protein level, AKT3 shows overall 83.6% identity with AKT1 and 78% identity with AKT2. The three AKT kinases are identical in the ATP binding region, except for one residue: Ala 230 of AKT1 is conserved in AKT2 (Ala 232), but switches to Val 228 in AKT3.

Mutations

Note No germline or somatic mutations were discovered through sequencing.

Implicated in

Entity Breast Cancer
Oncogenesis AKT3 was found to be expressed at a higher level in estrogen receptor-negative breast cancer compared to estrogen receptor-positive cancers, thus possibly contributing to the more aggressive phenotype of the former. AKT3 activity was also 30-to 60-fold higher in two estrogen receptor-negative cell lines as compared to two estrogen receptor-positive cell lines.
  
Entity Hepatocellular carcinoma (Hepatitis C virus related)
Oncogenesis Using array-CGH analysis, gene copy number increases of AKT3 were found in 6 out of 19 (32%) tumors, including small, well-differentiated carcinomas. Thus, increased copies of the gene may play a potentially important role in the onset of Hepatitis C-related hepatocellular carcinoma.
  
Entity Melanoma
Oncogenesis AKT3 was demonstrated to be the predominant AKT isoform involved in melanoma tumorigenesis. Knockdown of AKT3 with siRNA was shown to decrease total phospho-AKT levels in four melanoma cell lines and in normal melanocytes. In contrast, targeting the other two AKT proteins had no effect. AKT3 protein was overexpressed in 60% of primary melanoma tumors compared to normal melanocytes. Immunoprecipitation of AKT3 followed by immunoblotting with a phospho-specific AKT antibody indicated that 43% of primary melanomas have increased AKT3 activity compared to normal controls. Moreover, siRNA-mediated knockdown of AKT3 in a melanoma cell line led to a dramatic decrease in xenograft tumor size as a result of increased apoptosis.
  
Entity Ovarian Cancer
Oncogenesis AKT3 was discovered to be highly expressed in 19 out of 92 (20%) primary ovarian tumors and also expressed in a number of ovarian tumor cell lines, including two cell lines having duplications of the AKT3 gene. The high expression of AKT3 in cell lines appeared to correlate with high total phospho-AKT levels, increased proliferation, and the ability to grow in serum starved conditions. SiRNA-mediated silencing of AKT3 expression in the OVCA429 and DOV13 cell lines resulted in reduced proliferation due to inhibition of the cell cycle.
  
Entity Prostate Cancer
Oncogenesis AKT3 was found to be expressed at a higher level and with a 20- to 40-fold higher activity in androgen-insensitive prostate cancer compared to androgen-sensitive prostate cancer. The loss of PTEN expression appeared to contribute to increased AKT3 activity in one of the cell lines examined. Thus, AKT3 may play a role in the more aggressive phenotype of androgen-insensitive prostate cancers.
  

External links

Nomenclature
HGNC (Hugo)AKT3   393
Cards
AtlasAKT3ID615ch1q44
Entrez_Gene (NCBI)AKT3  10000  v-akt murine thymoma viral oncogene homolog 3
GeneCards (Weizmann)AKT3
Ensembl (Hinxton)ENSG00000117020 [Gene_View]  chr1:243663021-244006886 [Contig_View]  AKT3 [Vega]
AceView (NCBI)AKT3
Genatlas (Paris)AKT3
WikiGenes10000
SOURCE (Princeton)NM_001206729 NM_005465 NM_181690
Genomic and cartography
GoldenPath (UCSC)AKT3  -  1q43   chr1:243663021-244006886 -  1q44   [Description]    (hg19-Feb_2009)
EnsemblAKT3 - 1q44 [CytoView]
Mapping of homologs : NCBIAKT3 [Mapview]
OMIM603387   611223   
Gene and transcription
Genbank (Entrez)AF085234 AF124141 AF135794 AJ245709 AK055109
RefSeq transcript (Entrez)NM_001206729 NM_005465 NM_181690
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_029764 NT_167186 NW_001838553 NW_004929294
Consensus coding sequences : CCDS (NCBI)AKT3
Cluster EST : UnigeneHs.498292 [ NCBI ]
CGAP (NCI)Hs.498292
Alternative Splicing : Fast-db (Paris)GSHG0003089
Alternative Splicing GalleryENSG00000117020
Gene ExpressionAKT3 [ NCBI-GEO ]     AKT3 [ SEEK ]   AKT3 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y243 (Uniprot)
NextProtQ9Y243  [Medical]
With graphics : InterProQ9Y243
Splice isoforms : SwissVarQ9Y243 (Swissvar)
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)AGC_KINASE_CTER (PS51285)    PH_DOMAIN (PS50003)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)AGC-kinase_C    Kinase-like_dom    PH_like_dom    Pkinase_C    Pleckstrin_homology    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_dual-sp_kinase_dom    Ser/Thr_kinase_AS   
Related proteins : CluSTrQ9Y243
Domain families : Pfam (Sanger)PH (PF00169)    Pkinase (PF00069)    Pkinase_C (PF00433)   
Domain families : Pfam (NCBI)pfam00169    pfam00069    pfam00433   
Domain families : Smart (EMBL)PH (SM00233)  S_TK_X (SM00133)  S_TKc (SM00220)  
DMDM Disease mutations10000
Blocks (Seattle)Q9Y243
PDB (SRS)2X18   
PDB (PDBSum)2X18   
PDB (IMB)2X18   
PDB (RSDB)2X18   
Human Protein AtlasENSG00000117020
Peptide AtlasQ9Y243
HPRD06441
IPIIPI00031747   IPI00219411   IPI01021636   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y243
IntAct (EBI)Q9Y243
FunCoupENSG00000117020
BioGRIDAKT3
InParanoidQ9Y243
Interologous Interaction database Q9Y243
IntegromeDBAKT3
STRING (EMBL)AKT3
Ontologies - Pathways
Ontology : AmiGOmitochondrial genome maintenance  protein kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  phospholipid binding  nucleus  nucleolus  cytoplasm  Golgi apparatus  plasma membrane  protein phosphorylation  signal transduction  
Ontology : EGO-EBImitochondrial genome maintenance  protein kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  phospholipid binding  nucleus  nucleolus  cytoplasm  Golgi apparatus  plasma membrane  protein phosphorylation  signal transduction  
Pathways : KEGGMAPK signaling pathway    ErbB signaling pathway    Ras signaling pathway    Rap1 signaling pathway    Chemokine signaling pathway    HIF-1 signaling pathway    FoxO signaling pathway    mTOR signaling pathway    PI3K-Akt signaling pathway    Apoptosis    Adrenergic signaling in cardiomyocytes    VEGF signaling pathway    Osteoclast differentiation    Focal adhesion    Tight junction    Toll-like receptor signaling pathway    Jak-STAT signaling pathway    T cell receptor signaling pathway    B cell receptor signaling pathway    Fc epsilon RI signaling pathway    Fc gamma R-mediated phagocytosis    TNF signaling pathway    Neurotrophin signaling pathway    Cholinergic synapse    Dopaminergic synapse    Insulin signaling pathway    Progesterone-mediated oocyte maturation    Estrogen signaling pathway    Prolactin signaling pathway    Thyroid hormone signaling pathway    Adipocytokine signaling pathway    Non-alcoholic fatty liver disease (NAFLD)    Carbohydrate digestion and absorption    Chagas disease (American trypanosomiasis)    Toxoplasmosis    Tuberculosis    Hepatitis C    Hepatitis B    Measles    Influenza A    HTLV-I infection    Epstein-Barr virus infection    Pathways in cancer    Proteoglycans in cancer    Colorectal cancer    Renal cell carcinoma    Pancreatic cancer    Endometrial cancer    Glioma    Prostate cancer    Melanoma    Chronic myeloid leukemia    Acute myeloid leukemia    Small cell lung cancer    Non-small cell lung cancer   
REACTOMEAKT3
Protein Interaction DatabaseAKT3
Wikipedia pathwaysAKT3
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)AKT3
SNP (GeneSNP Utah)AKT3
SNP : HGBaseAKT3
Genetic variants : HAPMAPAKT3
1000_GenomesAKT3 
ICGC programENSG00000117020 
Somatic Mutations in Cancer : COSMICAKT3 
CONAN: Copy Number AnalysisAKT3 
Mutations and Diseases : HGMDAKT3
OMIM603387    611223   
GENETestsAKT3
Disease Genetic AssociationAKT3
Huge Navigator AKT3 [HugePedia]  AKT3 [HugeCancerGEM]
Genomic VariantsAKT3  AKT3 [DGVbeta]
Exome VariantAKT3
dbVarAKT3
ClinVarAKT3
snp3D : Map Gene to Disease10000
General knowledge
Homologs : HomoloGeneAKT3
Homology/Alignments : Family Browser (UCSC)AKT3
Phylogenetic Trees/Animal Genes : TreeFamAKT3
Chemical/Protein Interactions : CTD10000
Chemical/Pharm GKB GenePA24686
Clinical trialAKT3
Cancer Resource (Charite)ENSG00000117020
Other databases
Probes
Litterature
PubMed104 Pubmed reference(s) in Entrez
CoreMineAKT3
iHOPAKT3

Bibliography

Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3.
Masure S, Haefner B, Wesselink JJ, Hoefnagel E, Mortier E, Verhasselt P, Tuytelaars A, Gordon R, Richardson A
European journal of biochemistry / FEBS. 1999 ; 265 (1) : 353-360.
PMID 10491192
 
Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines.
Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ, Roth RA
The Journal of biological chemistry. 1999 ; 274 (31) : 21528-21532.
PMID 10419456
 
Mapping of AKT3, encoding a member of the Akt/protein kinase B family, to human and rodent chromosomes by fluorescence in situ hybridization.
Murthy SS, Tosolini A, Taguchi T, Testa JR
Cytogenetics and cell genetics. 2000 ; 88 (1-2) : 38-40.
PMID 10773662
 
Two splice variants of protein kinase B gamma have different regulatory capacity depending on the presence or absence of the regulatory phosphorylation site serine 472 in the carboxyl-terminal hydrophobic domain.
Brodbeck D, Hill MM, Hemmings BA
The Journal of biological chemistry. 2001 ; 276 (31) : 29550-29558.
PMID 11387345
 
AKT-1, -2, and -3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon.
Zinda MJ, Johnson MA, Paul JD, Horn C, Konicek BW, Lu ZH, Sandusky G, Thomas JE, Neubauer BL, Lai MT, Graff JR
Clinical cancer research : an official journal of the American Association for Cancer Research. 2001 ; 7 (8) : 2475-2479.
PMID 11489829
 
A portrait of AKT kinases: human cancer and animal models depict a family with strong individualities.
Bellacosa A, Testa JR, Moore R, Larue L
Cancer biology & therapy. 2004 ; 3 (3) : 268-275.
PMID 15034304
 
Analysis of DNA copy number aberrations in hepatitis C virus-associated hepatocellular carcinomas by conventional CGH and array CGH.
Hashimoto K, Mori N, Tamesa T, Okada T, Kawauchi S, Oga A, Furuya T, Tangoku A, Oka M, Sasaki K
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2004 ; 17 (6) : 617-622.
PMID 15133472
 
Deregulated Akt3 activity promotes development of malignant melanoma.
Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, Kester M, Sandirasegarane L, Robertson GP
Cancer research. 2004 ; 64 (19) : 7002-7010.
PMID 15466193
 
Perturbations of the AKT signaling pathway in human cancer.
Altomare DA, Testa JR
Oncogene. 2005 ; 24 (50) : 7455-7464.
PMID 16288292
 
A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)-M phase transition.
Cristiano BE, Chan JC, Hannan KM, Lundie NA, Marmy-Conus NJ, Campbell IG, Phillips WA, Robbie M, Hannan RD, Pearson RB
Cancer research. 2006 ; 66 (24) : 11718-11725.
PMID 17178867
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written07-2007Mitchell Cheung, Joseph R. Testa
Human Genetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

Citation

This paper should be referenced as such :
Cheung M, Testa JR . AKT3 (v-akt murine thymoma viral oncogene homolog 3, Protein Kinase B gamma). Atlas Genet Cytogenet Oncol Haematol. July 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/AKT3ID615ch1q44.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/38468/1/07-2007-AKT3ID615ch1q44.pdf   [ Bibliographic record ]

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Fri Apr 18 17:42:11 CEST 2014

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