Disease relevance of AKT2

• In addition, downstream effectors of PI3-kinase, AKT1 and AKT2, have been found to be amplified or activated in human tumours, including ovarian cancer [1].
• Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma [2].
• Confocal microscopy performed on transfected human breast cancer cells showed that unlike AKT1, AKT2 protein predominantly localized adjacent to the collagen IV matrix during cellular attachment [3].
• Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells [3].
• AKT2 is a serine/threonine kinase implicated in human ovarian and pancreatic cancers [4].
• Although heterozygous loss-of- function mutations in AKT2 can cause a syndrome of severe insulin resistance and lipodystrophy in humans, such mutations are uncommon causes of these syndromes [5].

High impact information on AKT2

• An insulin-like signaling pathway, from the DAF-2 receptor, the AGE-1 phosphoinositide 3-kinase, and the AKT-1/AKT-2 serine/threonine kinases to the DAF-16 Fork head transcription factor, regulates the metabolism, development, and life span of Caenorhabditis elegans [6].
• Akt2, phosphatidylinositol 3-kinase, and PTEN are in lipid rafts of intestinal cells: role in absorption and differentiation [7].
• In Caco-2 cells, while EGF stimulated BB NHE3, Akt2 was active in both LR and DS pools [7].
• Akt2 also correlated with epithelial cell differentiation [7].
• These results also suggest that LR-associated Akt2 may be involved in enterocyte differentiation [7].

Chemical compound and disease context of AKT2

• The rats bearing well-established C6 gliomas were treated with LXSN-AS-AKT2 DNA or LXSN (empty vector)-lipofectamine complexes intratumorally (treated group and control treated group) [8].
• Akt2, a homolog of Akt1, encodes a serine/threonine protein kinase that is amplified in ovarian and pancreatic cancers [9].
• In this report we now show that overexpression of EGFR or activated AKT-2 in MCF-7 cells leads to phosphorylation of Ser167 in the AF-1 domain of ERalpha, enhanced ER-amplified in breast cancer 1 (ER:AIB1) interaction in the presence of tamoxifen, and resistance to tamoxifen [10].
• CONCLUSION: Taken together, these results suggest that specific Akt isoforms such as Akt2 and Akt3 might be involved in chemoresistance to cisplatin and that these isoforms could be putative targets for gene therapy in uterine cancers [11].

Biological context of AKT2

• Two human homologues of the v-akt oncogene, AKT1 and AKT2, were cloned [2].
• The kinase activity and the phosphorylation of AKT2 were induced by the growth factors and blocked by the phosphatidylinositol (PI) 3-kinase inhibitor, wortmannin, and dominant-negative Ras (N17Ras) [12].
• AKT2 transfectants demonstrated increased adhesion and invasion through collagen IV because of up-regulation of beta1 integrins [3].
• Targeted reduction of AKT1 expression, but not AKT2, by RNA interference resulted in an abnormal epidermis in organotypic skin cultures with a thin parabasal region and a pronounced but disorganized cornified layer [13].
• Ectopic expression of constitutively active AKT2 and/or survivin significantly rescue human cancer cells from GGTI-298-induced apoptosis [14].

Anatomical context of AKT2

• In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor alpha (TNFalpha) through a phosphatidylinositol 3-kinase-dependent pathway [15].
• AKT activity increased during keratinocyte differentiation and was attributed to the specific activation of AKT1 and AKT2 [13].
• Phosphorylated AKT2 in tumor specimens localized to the cell membrane and cytoplasm but not the nucleus [16].
• APPL is highly expressed in skeletal muscle, heart, ovary and pancreas, tissues in which AKT2 mRNA is abundant [4].
• It has been observed that the expression levels of AKT1, AKT2, and AKT3 vary, but the levels of phospho-Ser473 AKT and phospho-Thr308 AKT are quite unique in these cancer cell lines, and that CL-1 cells have the highest basal levels of AKT activation among these cell lines [17].

Associations of AKT2 with chemical compounds

• Increased invasion by AKT2 was blocked by preincubation with an anti-beta1 integrin function blocking antibody, exposure to wortmannin, and by expression of phosphatase and tensin homologue tumor suppressor (PTEN) [3].
• Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2 [4].
• Genistein may also act by disabling cancer cell self-protection by inhibiting expression of AKT2, CYP1B1, and DNA ligase III [18].
• Sequence analysis and in vitro translation demonstrated that AKT2 encodes a 56-kDa protein with homology to serine/threonine kinases; moreover, this protein contains a Src homology 2-like domain [19].
• Importantly, expression of constitutively active AKT1 or AKT2 does not rescue cells from the imatinib-mediated apoptosis although glucose uptake was not blocked, suggesting that the potential therapeutic effect of imatinib is independent of AKT activity and glucose deprivation [20].

Enzymatic interactions of AKT2

• AKT2 interacts with and phosphorylates ASK1 at Ser-83 resulting in inhibition of its kinase activity [21].
• Sequence analysis suggested that p38 MAPK could not directly phosphorylate Akt2 [22].

Regulatory relationships of AKT2

• Western blot analysis revealed loss of PTEN protein expression in two of the 12 pancreatic carcinomas with activated AKT2 [23].
• Inhibition of JNK by cellular stress- and tumor necrosis factor alpha-induced AKT2 through activation of the NF kappa B pathway in human epithelial Cells [15].
• Interestingly, down-regulation of Akt2 suppressed the EMT-like morphological conversion induced by Akt1 down-regulation in IGF-IR-overexpressing cells and inhibited migration in EGF-stimulated cells [24].
• Insulin-like growth factor-I receptor (IGF-IR) hyperstimulation induced hyperproliferation and antiapoptotic activities that were reversed by Akt2 down-regulation [24].
• Only Akt1 Is Required for Proliferation, while Akt2 Promotes Cell Cycle Exit through p21 Binding [25].

Other interactions of AKT2

• The identification of APPL may facilitate further analysis of the physiological and oncogenic activities of AKT2 [4].
• The PIK3CA gene encodes the p110alpha catalytic subunit of PI3K, and is amplified in some ovarian cancers, whereas the AKT2 gene is amplified in some ovarian, breast, and pancreatic cancers [26].
• Results: Overall, we detected three somatic mutations in AKT2, but no mutations in AKT1 or AKT3 in the 294 cancer tissues [27].
• Over-expression of constitutively active Akt2 and MKK1 blocked alpha-TEA-induced apoptosis [28].
• Robust activation of Akt2 by EGF was observed in some cell lines in a PI3K-dependent manner [29].
• Reintroducing AKT2 largely rescued the phenotype resulted from knockdown of Twist in I4 cells, suggesting that AKT2 is a downstream target and functional mediator of Twist [30].

Analytical, diagnostic and therapeutic context of AKT2

• Immunostaining and Western blot analyses using a phospho-ser-473 Akt antibody that detects the activated form of AKT2 (AKT2 phosphorylated at serine-474) confirmed the frequent activation of AKT2 in ovarian cancer specimens [16].
• For this purpose, PIK3CA and AKT2 gene amplification was assessed by multiplex and Quantitative Real-Time PCR [31].
• Akt2 activity was evaluated by electrophoretic mobility shift assays [29].
• In contrast, akt2(-/-) mice displayed normal cardiac growth responses to provocative stimulation, including ligand stimulation of cultured cardiomyocytes, pressure overload by transverse aortic constriction, and myocardial infarction [32].
• AKT2 was mapped to chromosome region 19q13.1-q13.2 by fluorescence in situ hybridization [19].

References