Oncogenic transformation induced by membrane-targeted Akt2 and Akt3

Mende, Ines; Malstrom, Scott; Tsichlis, Philip N.; Vogt, Peter K.; Aoki, Masahiro

doi:10.1038/sj.onc.1204486

Cited by 94 publications

(73 citation statements)

References 51 publications

(53 reference statements)

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“…For instance, when AKT2 is myristoylated--a posttranslational modification that makes AKT2 membrane-associated--it leads to constitutively activated AKT2 in transfected cells (29,30). Furthermore, when myristoylated AKT2 is expressed in cells, it results in loss of contact inhibition and leads to focus formation, an indicator of oncogenicity (31). Similarly, AKT1 mutation (E17K) in the PH domain found in breast and ovarian cancer patients leads to membrane-bound and constitutively activated AKT1 with increased focus formation (32).…”

Section: Discussionmentioning

confidence: 99%

Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma

Kannan

Coarfa

Chao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Here we report a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of the 60 patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. Further, we provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient's tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells. Unlike endogenous AKT2, whose activity is tightly regulated by external stimuli, BCAM-AKT2 escapes the regulation from external stimuli. Moreover, a BCAM-AKT2 fusion gene generated via chromosomal translocation using the CRISPR/Cas9 system leads to focus formation in both OVCAR8 and HEK-293T cell lines, suggesting that BCAM-AKT2 is oncogenic. Together, the results indicate that BCAM-AKT2 expression is a new mechanism of AKT2 kinase activation in HGSC. BCAM-AKT2 is the only fusion gene in HGSC that is proven to translate an aberrant yet functional kinase fusion protein with oncogenic properties. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC.cancer-specific fusion gene | high-grade serous ovarian cancer | AKT2 | BCAM | fusion kinase O varian cancer is responsible for the death of ∼140,200 women yearly, and 70% of these deaths are due to the high-grade serous ovarian cancer (HGSC) subtype (1), which is typically detected only after it has metastasized. Genomic characterization of HGSC tumors shows that TP53 mutations are present in 96% and BRCA1/2 in 22% of HGSC (2). These mutations are thought to occur early in pathogenesis (3) and promote genomic instability, thus giving rise to the high degree of heterogeneity and genomic rearrangements that are characteristic of these cancers. The characteristic genome rearrangements in HGSC imply that recombination events such as gene fusions should be common. Moreover, if the activity of a fusion gene represents a common oncogenic mechanism, the same fusion gene is likely to occur in many patients.Recurrent fusion genes are important for understanding cancer mechanisms and developing useful clinical biomarkers and anticancer therapies. For instance, the BCR-ABL fusion gene in chronic myeloid leukemia is known to initiate oncogenesis through formation of a misregulated BCR-ABL fusion kinase. The BCR-ABL fusion gene is also a clinical biomarker of high diagnostic and prognostic utility in chronic myeloid leukemia. In addition, this fusion protein serves as a therapeutic target for the successful drug imatinib (4). In solid human tumors, fusion genes such as the TMPRSS2-ERG fusion in prostate cancer (5), FGFR-TACC in glioblastoma (6), and DNAJB1...

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Section: Discussionmentioning

confidence: 99%

Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma

Kannan

Coarfa

Chao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The tumor surface phenotype was variable with some expressing a CD4 or CD8 SP, and some expressing a CD4͞CD8 DP phenotype. Interestingly, an Lck-MyrAkt2 transgene is equally oncogenic with the Lck-MyrAkt1 transgene described here (27). To determine why the MyrAkt and AktE40K transgenes differ in oncogenic potential, we first examined whether they differ in their ability to inhibit apoptosis induced by growth factor (IL-2 and Con A Sup) withdrawal.…”

Section: Myrakt and Akte40kmentioning

confidence: 99%

Tumor induction by an Lck-MyrAkt transgene is delayed by mechanisms controlling the size of the thymus

Malstrom

Tili

Kappes

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Transgenic mice expressing MyrAkt from a proximal Lck promoter construct develop thymomas at an early age, whereas transgenic mice expressing constitutively active Lck-AktE40K develop primarily tumors of the peripheral lymphoid organs later in life. The thymus of 6-to 8-week-old MyrAkt transgenic mice is normal in size but contains fewer, larger cells than the thymus of nontransgenic control and AktE40K transgenic mice. Earlier studies had shown that cell size and cell cycle are coordinately regulated. On the basis of this finding, and our observations that the oncogenic potential of Akt correlates with its effect on cell size, we hypothesized that mechanisms aimed at maintaining the size of the thymus dissociate cell size and cell cycle regulation by blocking MyrAkt-promoted G1 progression and that failure of these mechanisms may promote cell proliferation resulting in an enlarged neoplastic thymus. To address this hypothesis, we examined the cell cycle distribution of freshly isolated and cultured thymocytes from transgenic and nontransgenic control mice. The results showed that although neither transgene alters cell cycle distribution in situ, the MyrAkt transgene promotes G1 progression in culture. Freshly isolated MyrAkt thymocytes express high levels of cyclins D2 and E and cdk4 but lower than normal levels of cyclin D3 and cdk2. Cultured thymocytes from MyrAkt transgenic mice, on the other hand, express high levels of cyclin D3, suggesting that the hypothesized organ size control mechanisms may down-regulate the expression of this molecule. Primary tumor cells, similar to MyrAkt thymocytes in culture, express high levels of cyclin D3. These findings support the hypothesis that tumor induction is caused by the failure of organ size control mechanisms to downregulate cyclin D3 and to block MyrAkt-promoted G1 progression.

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“…AKTs are major downstream targets of growth factor receptors that signal through phosphatidylinositol 3-kinase (Testa and Bellacosa, 2001). Mounting evidence exists that activation of AKT proteins is important in cancer development (Muise-Helmericks et al, 1998;Dimmeler et al, 1999;Khwaja, 1999;Ozes et al, 1999;Mende et al, 2001;Wei et al, 2001). PTEN inhibits AKT activation and works as a tumour suppressor (Testa and Bellacosa, 2001).…”

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confidence: 99%

Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias

et al. 2008

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Mounting evidence indicates that alterations of AKT signalling play important roles in cancer development. An earlier study discovered an oncogenic AKT1 gene mutation (AKT1 E17K) in breast, colorectal and ovarian cancers. The aim of this study was to see whether the AKT1 E17K mutation is common in breast, colorectal, lung, gastric and hepatocellular carcinomas and acute leukaemias. We analysed the presence of the AKT1 E17K mutation in 731 cancer tissues by a single-strand conformation polymorphism assay. In addition, we analysed the corresponding sequences of AKT1 E17K in AKT2 and AKT3 genes. Overall, we detected the four AKT1 E17K mutations in the breast cancers (4/93; 4.3%), but none in other cancers. There was no AKT2 or AKT3 mutation in the cancers. This study demonstrated that the AKT1 E17K mutation occurs in breast cancers at a low frequency, and that it is rare in other common cancers, including colorectal, lung, gastric and hepatocellular carcinomas and acute leukaemias. Despite the confirmed oncogenic function of the AKT1 E17K, the rare incidences of the mutation suggest that it may not play a crucial role in the development of the most common types of human cancers. (Gschwind et al, 2004). AKT1 (also known as protein kinase B) is a subfamily of serine/threonine protein kinases, and the AKT genes are the mammalian equivalent of murine viral oncogene v-akt (Testa and Bellacosa, 2001). There are three isoforms of the AKT (AKT1, AKT2 and AKT3), and each AKT member contains an N-terminal pleckstrin homology (PH) domain, a short a-helical linker and a C-terminal kinase domain (Testa and Bellacosa, 2001). AKTs are major downstream targets of growth factor receptors that signal through phosphatidylinositol 3-kinase (Testa and Bellacosa, 2001). Mounting evidence exists that activation of AKT proteins is important in cancer development (Muise-Helmericks et al, 1998;Dimmeler et al, 1999;Khwaja, 1999;Ozes et al, 1999;Mende et al, 2001;Wei et al, 2001). PTEN inhibits AKT activation and works as a tumour suppressor (Testa and Bellacosa, 2001). Inactivating mutation of PTEN and activating mutation of PIK3CA have been detected in many human cancers and have been known as major activating mechanisms of AKTsignalling pathway in cancers (Testa and Bellacosa, 2001;Samuels et al, 2004). By contrast, activating mutation of AKT genes has not been widely reported in human cancers.Recently, a research group discovered a recurrent somatic mutation of AKT1 gene in human breast, colorectal and ovarian cancers (Carpten et al, 2007). The AKT1 mutation was a missense mutation that substituted an amino acid (E17K) in the PH domain of AKT1. The AKT1 E17K mutation was found in 5 out of 61 (8.2%) breast cancers, 3 out of 51 (5.9%) colorectal cancers and 1 out of 50 (2.0%) ovarian cancers (Carpten et al, 2007). The E17K mutation was mutually exclusive with respect to PIK3CA mutation and loss of PTEN expression (Carpten et al, 2007). Functionally, the AKT1 E17K mutation stimulates AKT signalling, induces cellular transformation and produ...

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Oncogenic transformation induced by membrane-targeted Akt2 and Akt3

Cited by 94 publications

References 51 publications

Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma

Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma

Tumor induction by an Lck-MyrAkt transgene is delayed by mechanisms controlling the size of the thymus

Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias

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