Akt is negatively regulated by the MULAN E3 ligase

Bae, Seunghee; Kim, Sun Yong; Jung, Jin Hyuk; Yoon, Younju; Jun, Hwa; Lee, Hyunjin; Kim, Karam; Kim, Jongran; An, In Sook; Kim, Jong-Doo; Um, Hong Duck; Park, In-Cheol; Lee, Su Jae; Nam, Sang Yong; Jin, Young Woo; Lee, Jae Ho; An, Sungkwan

doi:10.1038/cr.2012.38

Cited by 86 publications

(111 citation statements)

References 49 publications

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“…Those mechanisms involve AKT dephosphorylation by a variety of phosphatases [13][14][15][16][17] or its degradation by E3 ligases. 18,19 We describe here the identification of HPIP as a MDM2 substrate. HPIP degradation by MDM2 occurs through a p53-independent pathway and on phosphorylation by TBK1, an IKK-related kinase described as a synthetic lethal partner of KRAS and as a pro-angiogenic factor.…”

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confidence: 99%

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

et al. 2014

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Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because the MDM2 targetome extends beyond p53, MDM2 inhibition may also cause unwanted activation of oncogenic pathways. Accordingly, we identified the microtubuleassociated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Importantly, decreasing Mdm2 gene dosage in mouse mammary epithelial cells potentiates estrogen-dependent AKT activation owing to HPIP stabilization. In addition, we identified HPIP as a novel p53 transcriptional target, and pharmacological inhibition of MDM2 causes p53-dependent increase in HPIP transcription and also prevents HPIP degradation by turning off TBK1 activity. Our data indicate that p53 reactivation through MDM2 inhibition may result in ectopic AKT oncogenic activity by maintaining HPIP protein levels. Cell Death and Differentiation (2014) 21, 811-824; doi:10.1038/cdd.2014.2; published online 31 January 2014Restoration of p53 tumor suppressor function in cancer cells expressing wild-type (WT) p53 is a promising therapeutic approach. 1 Reactivation of p53 activity can be achieved by small molecular inhibitors that disrupt the interaction between p53 and its main E3 ligase MDM2. As a result, targeted cells undergo cell cycle arrest and apoptosis through p53 stabilization. 2 A potential drawback associated with this approach is that, besides p53, MDM2 targets other substrates for degradation. 3 In this context, accumulative evidence show that MDM2 promotes the degradation of FOXO3a, a tumor-suppressing transcription factor as well as the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. 4,5 Although it is currently unclear whether MDM2 targets positive regulators of oncogenic pathways, an exhaustive characterization of MDM2 substrates will help to anticipate undesired side effects of MDM2 inhibitors used in cancer therapy.Oncogenic pathways include AKT-dependent signaling cascades. Indeed, AKT promotes cell proliferation, survival, migration and angiogenesis by targeting numerous substrates ranging from anti-apoptotic transcription factors to regulators of protein synthesis. 6,7 Mutations or altered expressions of various AKT-activating signaling molecules have been described in human malignancies, thereby defining AKT as a hallmark of tumor development and progression. 8,9 AKT activation by estrogens requires the microtubule-binding protein hematopoietic PBX-interaction protein (HPIP). 10 Initially identified as a corepressor of pre-B-cell leukemia homeobox protein 1 (PBX1), 11 HPIP assembles a signaling complex that connects the p85 subunit of PI3K and ERa to microtubules in order to properly activate AKT. 10 Likewise, HPIP also promotes the growth and differentiation of hematopoietic cells through AKT. 12 Because correct reg...

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confidence: 99%

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

et al. 2014

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“…MUL1-mediated protein ubiquitination likely plays an integrative role in graded stress responses, including proteasomal protein degradation, mitochondrial segregation, autophagy, and apoptosis. 20,39 The results obtained in the present study suggested potential roles for MUL1 and ULK1 in selenite-induced mitophagy, representing novel aspects of the beneficial effects of selenium for chemoprevention. …”

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confidence: 84%

“…In addition, ULK1 partially translocated to mitochondria. It is likely that under normal conditions, MUL1, as an E3 ligase, monitors the mitochondrial outer membrane quality 20,38,39 and prevents ULK1 from initiating mitophagy. However, under stress conditions, higher amounts of ROS within the intermembrane space promote ULK1 translocation to mitochondria to initiate mitophagy.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy

Guo

et al. 2015

Autophagy

123

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“…26 Recent reports have also linked ubiquitin conjugation to Akt stability and function. In this context, several E3 ligases responsible for regulating Akt ubiquitylation have been described, some of which trigger ubiquitin-dependent Akt degradation, 27,28 while others enhance Akt membrane recruitment and downstream activity. [29][30][31] Among other activities, Akt regulates cell cycle progression impinging at different levels.…”

Section: Introductionmentioning

confidence: 99%

Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle

et al. 2013

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Akt is negatively regulated by the MULAN E3 ligase

Cited by 86 publications

References 49 publications

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

Mitochondrial outer-membrane E3 ligase MUL1 ubiquitinates ULK1 and regulates selenite-induced mitophagy

Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle

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