The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas

Shoji, Keiko; Oda, Katsutoshi; Nakagawa, Shunsuke; Hosokawa, S; Nagae, Genta; Uehara, Yuriko; Sone, Kenbun; Miyamoto, Yukio; Hiraike, Haruko; Hiraike‐Wada, Osamu; Nei, Tomomi; Kawana, Kei; Kuramoto, Hiroyuki; Aburatani, Hiroyuki; Yano, Tetsu; Taketani, Yuji

doi:10.1038/sj.bjc.6605109

Cited by 152 publications

(110 citation statements)

References 29 publications

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“…Furthermore, recent evidence indicates that the molecular mechanism underlying activation of AKT1(E17K) is a broadened target lipid selectivity that allows high-affinity binding to PI(4,5)P2 (Landgraf et al, 2008). AKT1(E17K) mutation has been reported in various human cancers, including breast cancers, colorectal cancers, ovarian cancers, squamous cell carcinoma of the lung, endometrial carcinomas, urothelial carcinoma and bladder cancer, but not in other multiple human malignancies, including acute leukemias and liver cancers (Carpten et al, 2007;Kim et al, 2008;Mahmoud et al, 2008;Malanga et al, 2008;Mohamedali et al, 2008;Riener et al, 2008;Shoji et al, 2009;Zilberman et al, 2009;Askham et al, 2010). These studies suggested that AKT1(E17K) mutation occurs at a low frequency and in a tissue-specific manner.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells

et al. 2010

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Section: Introductionmentioning

confidence: 99%

Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells

et al. 2010

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“…This suggests that AKT's effect in EC initiation and progression does not emerge from gain-of-function mutations but rather from the activation of upstream proteins. However, while the great majority of ECs display multiple mutations in the PI3K/PTEN/Akt pathway, mutation in Akt1 has been demonstrated to be sufficient for oncogenic transformation (Shoji et al 2009). …”

Section: Cancermentioning

confidence: 99%

Expression, activation, and role of AKT isoforms in the uterus

Fabi¹,

Asselin²

2014

Reproduction

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The three isoforms of AKT: AKT1, AKT2, and AKT3, are crucial regulators of both normal and pathological cellular processes. Each of these isoforms exhibits a high level of homology and functional redundancy with each other. However, while being highly similar and structurally homologous, a rising amount of evidence is showing that each isoform possesses specific targets as well as preferential subcellular localization. The role of AKT has been studied extensively in reproductive processes, but isoform-specific roles are yet to be fully understood. This review will focus on the role of AKT in the uterus and its function in processes related to cell death and proliferation such as embryo implantation, decidualization, endometriosis, and endometrial cancer in an isoform-centric manner. In this review, we will cover the activation of AKT in various settings, localization of isoforms in subcellular compartments, and the effect of isoform expression on cellular processes. To fully understand the dynamic molecular processes taking place in the uterus, it is crucial that we better understand the physiological role of AKT isoforms as well as their function in the emergence of diseases.Reproduction (2014) 148 R85-R95

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“…We appreciate the attention given by Drs Dutt, Salvesen, Greulich, Sellers, Beroukhim and Meyerson to our recent publication 'The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas' (Shoji et al, 2009). In this article, we report a 2% mutational frequency of AKT1 (E17K) among 101 endometrial carcinomas.…”

Section: Sirmentioning

confidence: 79%

Reply: Somatic mutations are present in all members of the AKT family in endometrial carcinoma

et al. 2009

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Cancer Research UK Sir,We appreciate the attention given by Drs Dutt, Salvesen, Greulich, Sellers, Beroukhim and Meyerson to our recent publication 'The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas ' (Shoji et al, 2009). In this article, we report a 2% mutational frequency of AKT1 (E17K) among 101 endometrial carcinomas. We also described that these two AKT1 mutant tumours do not possess any mutations in PIK3CA, PTEN and K-Ras. Our report has proposed two issues to be clarified: (1) Are there any 'oncogenic' mutations in other AKT family members in endometrial carcinomas? (2) Are all the AKT family mutations mutually exclusive with other PI3 kinase-AKT-activating mutations?Including the data in their earlier report, Dutt et al (2008) revealed mutations in AKT2 and AKT3, as well as in AKT1. As for AKT1 (E17K) mutations, their data and our data are compatible, showing that AKT1 mutations were detected in 2% of the endometrioid subtype in endometrial cancer. Compared with the accumulative data in AKT1 (E17K) mutations, mutations in AKT2 and AKT3 are not well characterised. Carpten et al (2007) and Kim et al (2008) reported no E17K mutations in AKT2 and AKT3 in breast, colorectal, gastric, hepatocellular, lung carcinomas and acute leukaemias. Davies et al (2008) first reported AKT3 (E17K) mutations in melanoma at 1.5% frequency. Parsons et al (2005) found two mutations of AKT2 (S302G and R371H) in 204 colorectal cancer samples, and Soung et al (2006) reported one missense mutation (A377V) and two possible splice-site mutations in intron 11 of AKT2 in gastric and lung adenocarcinoma. However, the physiological role of AKT2 mutations, including those (D399N, R368C and D32H) reported by Dutt et al (2008), has not been validated yet. In addition, the AKT3 (E438D) mutation has not been reported in any type of tumours. It is important to clarify whether these rare AKT2/3 mutations cause an oncogenic effect in cancer.We previously reported that PIK3CA mutations frequently coexist with mutations in PTEN and/or KRAS, and suggested that the PIK3CA mutation might require another upstream input to fully activate the PI3K kinase -AKT pathway (Oda et al, 2005(Oda et al, , 2008. Their data of coexistent mutations in AKT1 (E17K) and KRAS (G13D) suggest that the KRAS mutation alone is insufficient for a full activation of the PI3 kinase -AKT pathway. Their data are not inconsistent with the hypothesis that the AKT1 (E17K) mutation and the PIK3CA mutation are mutually exclusive. The coexistent mutations of AKT3 and PIK3CA in one sample suggest that some types of AKT mutations (non-E17K) might coexist with PIK3CA mutations to enhance the activation of the PI3 kinase -AKT pathway. Further analyses are necessary to clarify the frequency of coexistent mutations in AKT1 (E17K), AKT2/3 and other mutations.Their current data and our data suggest that the PI3 kinase -AKT pathway is prevalently activated in endometrial cancer through various genetic alterations and their combinations. Further analyses...

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The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas

Cited by 152 publications

References 29 publications

Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells

Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells

Expression, activation, and role of AKT isoforms in the uterus

Reply: Somatic mutations are present in all members of the AKT family in endometrial carcinoma

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