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

Risso, Guillermo; Pelisch, Federico; Pozzi, Berta; Mammi, Pablo; Blaustein, Matı́as; Colman‐Lerner, Alejandro; Srebrow, Anabella

doi:10.4161/cc.26183

Cited by 42 publications

(25 citation statements)

References 64 publications

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“…SUMOylation has also been reported to modulate AKT phosphorylation [50,51] and kinase activity [52] and can regulate G1/S cell cycle transition and Bcl-x pre-mRNA splicing [53]. Recently, two studies showed that SETDB1-mediated AKT methylation can promote AKT phosphorylation and activation [54,55].…”

Section: Akt Post-translational Modificationsmentioning

confidence: 99%

“…For example, growth-factor-induced K63-linked ubiquitination within the PH domain of AKT triggers membrane localisation and kinase activation [ 48 , 49 ]. SUMOylation has also been reported to modulate AKT phosphorylation [ 50 , 51 ] and kinase activity [ 52 ] and can regulate G1/S cell cycle transition and Bcl-x pre-mRNA splicing [ 53 ]. Recently, two studies showed that SETDB1-mediated AKT methylation can promote AKT phosphorylation and activation [ 54 , 55 ].…”

Section: Akt Post-translational Modificationsmentioning

confidence: 99%

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Inhibitors in AKTion: ATP-competitive vs allosteric

Lazaro

Kostaras

Vivanco

2020

Biochemical Society Transactions

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Aberrant activation of the PI3K pathway is one of the commonest oncogenic events in human cancer. AKT is a key mediator of PI3K oncogenic function, and thus has been intensely pursued as a therapeutic target. Multiple AKT inhibitors, broadly classified as either ATP-competitive or allosteric, are currently in various stages of clinical development. Herein, we review the evidence for AKT dependence in human tumours and focus on its therapeutic targeting by the two drug classes. We highlight the future prospects for the development and implementation of more effective context-specific AKT inhibitors aided by our increasing knowledge of both its regulation and some previously unrecognised non-canonical functions.

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Section: Akt Post-translational Modificationsmentioning

confidence: 99%

Section: Akt Post-translational Modificationsmentioning

confidence: 99%

Inhibitors in AKTion: ATP-competitive vs allosteric

Lazaro

Kostaras

Vivanco

2020

Biochemical Society Transactions

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show abstract

“…Another biochemical analysis revealed that K301, like K276, is also a prevalent SUMO attachment site on Akt. Moreover, double mutation on K276 and K301 residues of Akt was found to attenuate Akt-regulated cellular processes independently of Akt phosphorylation [ 69 ]. Even though SUMOylation of Akt is critical for Akt activation, the mechanism accounting for its activation remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

“…It also suggests that deeper understanding of the roles of PTMs on the activation of different Akt isoforms over the course of cancer progression and metastasis could be beneficial for therapeutic outcomes. Limited evidence has been presented that K63-linked ubiquitination and SUMOylation can efficiently modify both Akt1 and Akt2 [ 62 , 64 , 69 ], suggesting that neither modification is the major contributor for the diverse functions of Akt1 and Akt2 in metastasis. Further effort is required to define what PTMs may be associated with the activation of distinct Akt isoforms.…”

Section: Introductionmentioning

confidence: 99%

Posttranslational regulation of Akt in human cancer

et al. 2014

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Akt regulates critical cellular processes including cell survival and proliferation, glucose metabolism, cell migration, cancer progression and metastasis through phosphorylation of a variety of downstream targets. The Akt pathway is one of the most prevalently hyperactivated signaling pathways in human cancer, thus, research deciphering molecular mechanisms which underlie the aberrant Akt activation has received enormous attention. The PI3K-dependent Akt serine/threonine phosphorylation by PDK1 and mTORC2 has long been thought to be the primary mechanism accounting for Akt activation. However, this regulation alone does not sufficiently explain how Akt hyperactivation can occur in tumors with normal levels of PI3K/PTEN activity. Mounting evidence demonstrates that aberrant Akt activation can be attributed to other posttranslational modifications, which include tyrosine phosphorylation, O-GlcNAcylation, as well as lysine modifications: ubiquitination, SUMOylation and acetylation. Among them, K63-linked ubiquitination has been shown to be a critical step for Akt signal activation by facilitating its membrane recruitment. Deficiency of E3 ligases responsible for growth factor-induced Akt activation leads to tumor suppression. Therefore, a comprehensive understanding of posttranslational modifications in Akt regulation will offer novel strategies for cancer therapy.

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“…Recently, AKT1, a major player in the phosphoinositide 3‐kinase (PI3K)/AKT cell survival pathway, has been shown to be differentially post‐translationally modified by SUMOylation, and that this modification increases the proportion of BCLX L :BCLX S via AS, consistent with its pro‐survival role. This function of AKT1 is independent of its well‐studied phosphorylation by phosphoinositide‐dependent protein kinase 1 (PDK1) (in response to PI3K activation) or mammalian target of rapamycin complex 2 (mTORC2) .…”

Section: Alternative Splicing or Mis‐splicing In Hmsmentioning

confidence: 99%

Splice factor mutations and alternative splicing as drivers of hematopoietic malignancy

Hahn

Venugopal

Scott

et al. 2014

Immunological Reviews

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Differential splicing contributes to the vast complexity of mRNA transcripts and protein isoforms that are necessary for cellular homeostasis and response to developmental cues and external signals. The hematopoietic system provides an exquisite example of this. Recently, discovery of mutations in components of the spliceosome in various hematopoietic malignancies (HMs) has led to an explosion in knowledge of the role of splicing and splice factors in HMs and other cancers. A better understanding of the mechanisms by which alternative splicing and aberrant splicing contributes to the leukemogenic process will enable more efficacious targeted approaches to tackle these often difficult to treat diseases. The clinical implications are only just starting to be realized with novel drug targets and therapeutic strategies open to exploitation for patient benefit.

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

Cited by 42 publications

References 64 publications

Inhibitors in AKTion: ATP-competitive vs allosteric

Inhibitors in AKTion: ATP-competitive vs allosteric

Posttranslational regulation of Akt in human cancer

Splice factor mutations and alternative splicing as drivers of hematopoietic malignancy

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