Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

Fukushima, Toshiaki; Yoshihara, Hidehito; Furuta, Haruka; Kamei, Hiroyasu; Hakuno, Fumihiko; Luan, Jing; Duan, Cunming; Saeki, Yasushi; Tanaka, Keiji; Iemura, Shun Ichiro; Natsume, Tohru; Chida, Kazuhiro; Nakatsu, Yusuke; Kamata, Hideaki; Asano, Tomohiko; Takahashi, Shin‐Ichiro

doi:10.1038/ncomms7780

Cited by 64 publications

(61 citation statements)

References 56 publications

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“…Glucose treatment on glucose-starved cells elevated cellular calcium level, which is associated with NEDD4 E3 ligase activation, providing an explanation why H3 ubiquitination is enhanced by glucose treatment. Moreover, we also identify that NEDD4 monoubiquitinates H3 at multiple sites, consistent with the capability of NEDD4 in triggering monoubiquitination on its substrates as IGF1R and IRS2 (refs 15, 32). Although NEDD4 has been controversially implicated in regulating AKT signalling3334 and AKT signalling may also participate in the regulation of H3 acetylation35, we did not find that AKT signalling is affected by NEDD4 knockdown in our glucose treatment experiments (treating glucose in glucose-starved cells) and sphere-forming experiments (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 84%

H3 ubiquitination by NEDD4 regulates H3 acetylation and tumorigenesis

Zhang

Rezaeian

et al. 2017

Nat Commun

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Dynamic changes in histone modifications under various physiological cues play important roles in gene transcription and cancer. Identification of new histone marks critical for cancer development is of particular importance. Here we show that, in a glucose-dependent manner, E3 ubiquitin ligase NEDD4 ubiquitinates histone H3 on lysine 23/36/37 residues, which specifically recruits histone acetyltransferase GCN5 for subsequent H3 acetylation. Genome-wide analysis of chromatin immunoprecipitation followed by sequencing reveals that NEDD4 regulates glucose-induced H3 K9 acetylation at transcription starting site and enhancer regions. Integrative analysis of ChIP-seq and microarray data sets also reveals a consistent role of NEDD4 in transcription activation and H3 K9 acetylation in response to glucose. Functionally, we show that NEDD4-mediated H3 ubiquitination, by transcriptionally activating IL1α, IL1β and GCLM, is important for tumour sphere formation. Together, our study reveals the mechanism for glucose-induced transcriptome reprograming and epigenetic regulation in cancer by inducing NEDD4-dependent H3 ubiquitination.

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Section: Discussionsupporting

confidence: 84%

H3 ubiquitination by NEDD4 regulates H3 acetylation and tumorigenesis

Zhang

Rezaeian

et al. 2017

Nat Commun

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“…NEFH has been linked to TNF , IGF1 and MBP [58–60], which are all deafness genes in the mouse [58, 61, 62], and binds to OTOF [47], which is involved in deafness in mice and humans [48–50]. NEDD4 binds to and ubiquitylates the products of the mouse deafness genes PTEN , SPRY2 and IRS2 [63–69], and two proteins implicated in deafness in both mice and humans, WBP2 and KCNQ1 [26, 40–44]…”

Section: Resultsmentioning

confidence: 99%

Whole exome sequencing in adult-onset hearing loss reveals a high load of predicted pathogenic variants in known deafness-associated genes and identifies new candidate genes

et al. 2018

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BackgroundDeafness is a highly heterogenous disorder with over 100 genes known to underlie human non-syndromic hearing impairment. However, many more remain undiscovered, particularly those involved in the most common form of deafness: adult-onset progressive hearing loss. Despite several genome-wide association studies of adult hearing status, it remains unclear whether the genetic architecture of this common sensory loss consists of multiple rare variants each with large effect size or many common susceptibility variants each with small to medium effects. As next generation sequencing is now being utilised in clinical diagnosis, our aim was to explore the viability of diagnosing the genetic cause of hearing loss using whole exome sequencing in individual subjects as in a clinical setting.MethodsWe performed exome sequencing of thirty patients selected for distinct phenotypic sub-types from well-characterised cohorts of 1479 people with adult-onset hearing loss.ResultsEvery individual carried predicted pathogenic variants in at least ten deafness-associated genes; similar findings were obtained from an analysis of the 1000 Genomes Project data unselected for hearing status. We have identified putative causal variants in known deafness genes and several novel candidate genes, including NEDD4 and NEFH that were mutated in multiple individuals.ConclusionsThe high frequency of predicted-pathogenic variants detected in known deafness-associated genes was unexpected and has significant implications for current diagnostic sequencing in deafness. Our findings suggest that in a clinic setting, efforts should be made to a) confirm key sequence results by Sanger sequencing, b) assess segregations of variants and phenotypes within the family if at all possible, and c) use caution in applying current pathogenicity prediction algorithms for diagnostic purposes. We conclude that there may be a high number of pathogenic variants affecting hearing in the ageing population, including many in known deafness-associated genes. Our findings of frequent predicted-pathogenic variants in both our hearing-impaired sample and in the larger 1000 Genomes Project sample unselected for auditory function suggests that the reference population for interpreting variants for this very common disorder should be a population of people with good hearing for their age rather than an unselected population.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0395-1) contains supplementary material, which is available to authorized users.

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“…Most of the studies that have examined NEDD4 in cancer have demonstrated an inverse relationship between NEDD4 and PTEN [12]. More recently, NEDD4 has been identified as the E3 ligase for proteins other than PTEN such as IRS-2 [11] and the prostate-specific androgen-inducible gene PMEPA1, which negatively regulates signaling through androgen receptor [19]. These studies provide additional mechanisms for the putative oncogenic role of NEDD4.…”

Section: Discussionmentioning

confidence: 99%

NEDD4 ubiquitin ligase is a putative oncogene in endometrial cancer that activates IGF-1R/PI3K/Akt signaling

Zhang

Goodfellow

et al. 2015

Gynecologic Oncology

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Objective The PI3K/Akt pathway is frequently dysregulated in endometrial cancer, the most common gynecologic malignancy. Emerging evidence identifies the ubiquitin ligase NEDD4 as a key regulator of the PI3K/Akt pathway via activation of insulin-like growth factor-1 receptor (IGF-1R). Our objective was to understand the role of NEDD4 in endometrial cancer. Methods NEDD4 expression was assessed by immunohistochemistry in a tissue microarray with 77 endometrial lesions ranging from normal benign endometrium to tumor specimens of varying stage and grade. Studies were extended to a panel of eight endometrial cancer cell lines phenotypically representing the most common endometrial patient tumors. Results Immunohistochemistry demonstrated robust staining of NEDD4 in endometrial tumor specimens, with greater NEDD4 expression in the most aggressive tumors. Expression of NEDD4 was detected in a majority of endometrial cancer cell lines surveyed. Exogenous overexpression of murine Nedd4 in endometrial cancer cell lines with modest endogenous NEDD4 expression resulted in a significant increase in the rate of proliferation. Nedd4 overexpression also promoted an increase in cell surface localization of IGF-1R and activation of Akt. Inhibition of PI3K/Akt signaling reversed the enhanced cell growth in Nedd4-overexpressing endometrial cancer cells. In addition, expression of NEDD4 in endometrial tumors positively correlated with the Akt downstream effector FoxM1. Conclusions This study identifies NEDD4 as a putative oncogene in endometrial cancer that may augment activation of the IGF-1R/PI3K/Akt signaling pathway.

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Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

Cited by 64 publications

References 56 publications

H3 ubiquitination by NEDD4 regulates H3 acetylation and tumorigenesis

H3 ubiquitination by NEDD4 regulates H3 acetylation and tumorigenesis

Whole exome sequencing in adult-onset hearing loss reveals a high load of predicted pathogenic variants in known deafness-associated genes and identifies new candidate genes

NEDD4 ubiquitin ligase is a putative oncogene in endometrial cancer that activates IGF-1R/PI3K/Akt signaling

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