A novel AKT3 mutation in melanoma tumours and cell lines

Davies, Michael A.; Stemke-Hale, Katherine; Tellez, Carmen S.; Calderone, Tiffany L.; Deng, Wuguo; Prieto, Víctor G.; Lazar, Alexander J.; Gershenwald, Jeffrey E.; Mills, Gordon B.

doi:10.1038/sj.bjc.6604637

Cited by 233 publications

(174 citation statements)

References 27 publications

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“…Its aberrant activation is contributed via a number of mechanisms including oncogenic alterations of components of the PI3 K pathway, such as mutations or amplification of the PI3 K subunits or inactivation of PTEN [19] and mutation of three PKB isoforms [20][21][22]. These mutations contribute to a multitude of human cancers, including breast cancer, colorectal cancer, ovarian cancer, lung cancer and melanoma.…”

Section: Pkb Activation Drives Cancer Developmentmentioning

confidence: 99%

PKB/Akt-dependent regulation of inflammation in cancer

Tang

Wang

Hemmings

et al. 2018

Seminars in Cancer Biology

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A B S T R A C TChronic inflammation is a major cause of human cancer. Clinical cancer therapies against inflammatory risk factors are strategically determined. To rationally guide a novel drug development, an improved mechanistic understanding on the pathological connection between inflammation and carcinogenesis is essential. PI3K-PKB signaling axis has been extensively studied and shown to be one of the key oncogenic drivers in most types of cancer. Pharmacological inhibition of the components along this signaling axis is of great interest for developing novel therapies. Interestingly, emerging studies have shown a close association between PKB activation and inflammatory activity in the vicinity of the tumor, and either blockade of PKB or attenuation of para-tumoral inflammation reveals a mutual-interactive pattern through pathway crosstalk. In this review, we intend to discuss recent advances of PKB-regulated chronic inflammation and its potential impacts on tumor development.

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Section: Pkb Activation Drives Cancer Developmentmentioning

confidence: 99%

PKB/Akt-dependent regulation of inflammation in cancer

Tang

Wang

Hemmings

et al. 2018

Seminars in Cancer Biology

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“…S4). Because AKT3 E17K mutations in melanoma (33) and AKT2 E17K mutations in human hypoglycemina (12) have been reported, we generated the E17K AKT2 and AKT3 mutants along with additional AKT2 and AKT3 somatic mutations that have been identified in human cancers ( Fig. 2A).…”

Section: Disruption Of Akt2 and Akt3 Ph-kd Interactions Leads To Theirmentioning

confidence: 99%

Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers

Parikh

Janakiraman

et al. 2012

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

130

160

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The protein kinase v-akt murine thymoma viral oncogene homolog (AKT), a key regulator of cell survival and proliferation, is frequently hyperactivated in human cancers. Intramolecular pleckstrin homology (PH) domain-kinase domain (KD) interactions are important in maintaining AKT in an inactive state. AKT activation proceeds after a conformational change that dislodges the PH from the KD. To understand these autoinhibitory interactions, we generated mutations at the PH-KD interface and found that most of them lead to constitutive activation of AKT. Such mutations are likely another mechanism by which activation may occur in human cancers and other diseases. In support of this likelihood, we found somatic mutations in AKT1 at the PH-KD interface that have not been previously described in human cancers. Furthermore, we show that the AKT1 somatic mutants are constitutively active, leading to oncogenic signaling. Additionally, our studies show that the AKT1 mutants are not effectively inhibited by allosteric AKT inhibitors, consistent with the requirement for an intact PH-KD interface for allosteric inhibition. These results have important implications for therapeutic intervention in patients with AKT mutations at the PH-KD interface.interdomain | AKT-targeting | PI3K-pathway | next generation sequencing | BaF3

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“…Akt1 E17K is constitutively activated by docking the Akt1 to the plasma membrane, thereby causing uncontrolled Akt signaling and, eventually, cell transformation (82). The same point mutations in Akt2 and Akt3 did not transform cells in vitro (82), although another group found an Akt3 E17K mutation in malignant melanoma cells (83).…”

Section: Akt1 Mutations and Cancermentioning

confidence: 99%

The Akt isoforms, their unique functions and potential as anticancer therapeutic targets

Santi¹,

Douglas²,

Lee³

2010

BioMolecular Concepts

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Akt (also known as protein kinase B or PKB) is the major downstream nodal point of the PI3K signaling pathway. This pathway is a promising anticancer therapeutic target, because constitutive activation of the PI3K-Akt pathway is correlated with tumor development, progression, poor prognosis, and resistance to cancer therapies. The Akt serine/threonine kinase regulates diverse cellular functions including cell growth, proliferation, glucose metabolism, and survival. Although all three known Akt isoforms (Akt1-3) are encoded by separate genes, their amino acid sequences show a high degree of similarity. For this and other reasons, it has long been assumed that all three Akt isoforms are activated in the same way, and their functions largely overlap. However, accumulating lines of evidence now suggest that the three Akt isoforms might have unique modes of activation and many distinct functions. In particular, it has recently been found that the Akt isoforms are localized at different subcellular compartments in both adipocytes and cancer cells. In this review, we highlight the unique roles of each Akt isoform by introducing published data obtained from both in vitro and in vivo studies. We also discuss the significant potential of the Akt isoforms as effective anticancer therapeutic targets.

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A novel AKT3 mutation in melanoma tumours and cell lines

Cited by 233 publications

References 27 publications

PKB/Akt-dependent regulation of inflammation in cancer

PKB/Akt-dependent regulation of inflammation in cancer

Disruption of PH–kinase domain interactions leads to oncogenic activation of AKT in human cancers

The Akt isoforms, their unique functions and potential as anticancer therapeutic targets

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