AKT3 (v-akt murine thymoma viral oncogene homolog 3, Protein Kinase B gamma)
2007-07-01 Mitchell Cheung , Joseph R. Testa AffiliationHuman Genetics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
Identity
HGNC
LOCATION
1q43
LOCUSID
ALIAS
MPPH,MPPH2,PKB-GAMMA,PKBG,PRKBG,RAC-PK-gamma,RAC-gamma,STK-2
FUSION GENES
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.
Proteins
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 name
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 name
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 name
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 name
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 name
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 16288292 | 2005 | Perturbations of the AKT signaling pathway in human cancer. | Altomare DA et al |
| 15034304 | 2004 | A portrait of AKT kinases: human cancer and animal models depict a family with strong individualities. | Bellacosa A et al |
| 11387345 | 2001 | 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 et al |
| 17178867 | 2006 | A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)-M phase transition. | Cristiano BE et al |
| 15133472 | 2004 | Analysis of DNA copy number aberrations in hepatitis C virus-associated hepatocellular carcinomas by conventional CGH and array CGH. | Hashimoto K et al |
| 10491192 | 1999 | Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3. | Masure S et al |
| 10773662 | 2000 | 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 et al |
| 10419456 | 1999 | Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. | Nakatani K et al |
| 15466193 | 2004 | Deregulated Akt3 activity promotes development of malignant melanoma. | Stahl JM et al |
| 11489829 | 2001 | AKT-1, -2, and -3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon. | Zinda MJ et al |
Other Information
Locus ID:
NCBI: 10000
MIM: 611223
HGNC: 393
Ensembl: ENSG00000117020
Variants:
dbSNP: 10000
ClinVar: 10000
TCGA: ENSG00000117020
COSMIC: AKT3
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA134890823 | PIK3R5 | Gene | Pathway | associated | |||
| PA248 | NFKB1 | Gene | Pathway | associated | |||
| PA254 | NOS3 | Gene | Pathway | associated | 20124951 | ||
| PA27749 | ELK1 | Gene | Pathway | associated | |||
| PA28212 | FOS | Gene | Pathway | associated | |||
| PA296 | RELA | Gene | Pathway | associated | |||
| PA30006 | JUN | Gene | Pathway | associated | |||
| PA31353 | MYC | Gene | Pathway | associated | |||
| PA31600 | NFKB2 | Gene | Pathway | associated | |||
| PA33304 | PIK3C2A | Gene | Pathway | associated | 20124951 | ||
| PA33305 | PIK3C2B | Gene | Pathway | associated | 20124951 | ||
| PA337 | STAT3 | Gene | Pathway | associated | |||
| PA338 | STAT5A | Gene | Pathway | associated | |||
| PA36042 | SP1 | Gene | Pathway | associated | |||
| PA36183 | STAT1 | Gene | Pathway | associated | |||
| PA36184 | STAT2 | Gene | Pathway | associated | |||
| PA36185 | STAT4 | Gene | Pathway | associated | |||
| PA36186 | STAT5B | Gene | Pathway | associated |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38147774 | 2024 | Mechanism through which the hsa-circ_0000992- hsa- miR- 936-AKT3 regulatory network promotes the PM(2.5)-induced inflammatory response in human bronchial epithelial cells. | 0 |
| 38396845 | 2024 | All Three AKT Isoforms Can Upregulate Oxygen Metabolism and Lactate Production in Human Hepatocellular Carcinoma Cell Lines. | 0 |
| 38396907 | 2024 | Autocrine Regulation of Interleukin-6 via the Activation of STAT3 and Akt in Cardiac Myxoma Cells. | 0 |
| 38528080 | 2024 | Differential prognostic values of the three AKT isoforms in acute myeloid leukemia. | 0 |
| 38759814 | 2024 | A spectrum of AKT3 activating mutations cause focal malformations of cortical development (FMCDs) in cortical organoids. | 0 |
| 38147774 | 2024 | Mechanism through which the hsa-circ_0000992- hsa- miR- 936-AKT3 regulatory network promotes the PM(2.5)-induced inflammatory response in human bronchial epithelial cells. | 0 |
| 38396845 | 2024 | All Three AKT Isoforms Can Upregulate Oxygen Metabolism and Lactate Production in Human Hepatocellular Carcinoma Cell Lines. | 0 |
| 38396907 | 2024 | Autocrine Regulation of Interleukin-6 via the Activation of STAT3 and Akt in Cardiac Myxoma Cells. | 0 |
| 38528080 | 2024 | Differential prognostic values of the three AKT isoforms in acute myeloid leukemia. | 0 |
| 38759814 | 2024 | A spectrum of AKT3 activating mutations cause focal malformations of cortical development (FMCDs) in cortical organoids. | 0 |
| 36562080 | 2023 | circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in small cell lung cancer. | 4 |
| 36943433 | 2023 | Downregulation of circ_0024028 inhibits IL-22-induced keratinocyte proliferation and migration by miR-486-3p/AKT3 axis. | 1 |
| 36982700 | 2023 | Autoantibodies against PIP4K2B and AKT3 Are Associated with Skin and Lung Fibrosis in Patients with Systemic Sclerosis. | 3 |
| 37088138 | 2023 | Detecting Low-Variant Allele Frequency Mosaic Pathogenic Variants of NF1, TSC2, and AKT3 Genes from Blood in Patients with Neurodevelopmental Disorders. | 1 |
| 37879895 | 2023 | Differential activation of AKT isoforms by growth factors in human myotubes. | 1 |
Citation
Mitchell Cheung ; Joseph R. Testa
AKT3 (v-akt murine thymoma viral oncogene homolog 3, Protein Kinase B gamma)
Atlas Genet Cytogenet Oncol Haematol. 2007-07-01
Online version: http://atlasgeneticsoncology.org/gene/615/akt3
