The Oncogenic Functions of MASTL Kinase

Marzec, Kamila A.; Burgess, Andrew

doi:10.3389/fcell.2018.00162

Cited by 32 publications

(33 citation statements)

References 83 publications

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“…Well-differentiated epithelial-like cells have high CNI, whereas low CNI cells have abnormally-shaped nuclei ( Figure 1D). Consistent with the idea that low CNI is a marker of cancer progression and aggressiveness, this score was strongly and negatively associated with the mRNA levels of genes previously implicated in breast tumorigenesis including MCM4 35 , MCM10 36 , FOXM1 37 , CCNE2 38 , and MASTL 39 (Figure 1B). In addition, besides median I1 as an average measure, heterogeneity measures including standard deviation and skewness of morphology scores were also identified in this core network module;…”

Section: Hybrid Network Topological Analysis Revealed Tumour Morpholosupporting

confidence: 83%

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Arias-Garcia

Rickman

Sero

et al. 2019

Preprint

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The shape, size, and architecture of the nucleus determines the output of transcriptional programmes. As such, the ability of the nucleus to resist deformation and maintain its shape is essential for homeostasis. Conversely, changes in nuclear shape can alter transcription and cell state. The ability of cells to deform their nuclei is also essential for cells to invade confined spaces. But how cells set the extent of nuclear deformability in response to their environment is unclear. Here we show that the cell-cell adhesion protein JAM3 regulates nuclear shape. In epithelial cells, JAM3 is required for maintenance of nuclear shape by organizing microtubule polymers and promoting LMNA stabilization in the nuclear membrane. Depletion of JAM3 in normal epithelial cells leads to dysmorphic nuclei, which leads to differentiation into a mesenchymal-like state. Inhibiting the actions of kinesins in JAM3 depleted cells restores nuclear morphology and prevents differentiation into the mesenchymal-like state. Critically, JAM3 expression is predictive of disease progression. Thus JAM3 is a molecule which allows cells to control cell fates in response to the presence of neighbouring cells by tuning the extent of nuclear deformability. 3 IntroductionNuclear shape, size and architecture define the biophysics of key cellular processes such as transcription, replication, mRNA export, and DNA damage repair 1-4 . But nuclei are malleable viscoelastic structures 5, 6 that are frequently being stretched, strained, and compressed both by extracellular forces 7 , and the internal cytoskeleton 8-12 . Mechanisms have evolved to maintain nuclear shape and genome organization when cells are exposed to these forces 13 .Indeed, dysregulation of nuclear shape is coincident with numerous diseases including: muscular dystrophies, heart disease, and aging disorders such as progeria [14][15][16][17][18] . Thus in many cells, maintaining nuclear shape is essential for homeostasis.But while clearly maintenance of nuclear shape, size, and genome organization is essential for cellular homeostasis, transcriptional programmes that alter cell fate can be engaged by altering nuclear morphology and architecture 1,5,[19][20][21][22] . For example, nuclei undergo extensive shape changes that drive differentiation during development 23 . One means by which alteration in nuclear shape affects transcription is by affecting the nuclear translocation dynamics of transcription factors such as YAP/TAZ and NF-κB 24, 25 . Thus while in some cell types nuclear shape and genome organization are robust to deformation, in other cell types the nucleus is highly deformable.The importance of maintaining nuclear shape for cell, tissue, and organism homeostasis is highlighted by the fact that changes in nuclear morphology and genome organization are associated with cancer 4, 26 . For example, nuclear rupture is frequently an oncogenic event 27,28 . Indeed, pathologists have used nuclear shape as a diagnostic for over a century 29 . Irregular nuclear shapes and sizes are hall...

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Section: Hybrid Network Topological Analysis Revealed Tumour Morpholosupporting

confidence: 83%

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Arias-Garcia

Rickman

Sero

et al. 2019

Preprint

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“…Thus, recent years have seen a growing interest in this area of cell cycle control as a source of potential clinical targets for cancer therapy. Indeed, inhibitors of the Cdk1 regulatory kinases Wee1/Myt1 show promising results in clinical trials , while the PP2A regulatory kinase Greatwall is attracting interest as a potential therapeutic target .…”

Section: The Mitotic Trigger Is An Irreversible Cellular Switchmentioning

confidence: 99%

“…High expression of Greatwall has been associated with poor prognosis in triple‐negative breast cancers and the PP2A regulator B55‐alpha is deleted in 15% of prostate cancers . Current models suggest that PP2A:B55 acts as a tumour suppressor, and cancer cells often employ high levels of Greatwall to downregulate this antiproliferative phosphatase activity . This has been suggested to sensitise cells to loss of Greatwall activity.…”

Section: Mitotic Entry and Cancermentioning

confidence: 99%

Triggering mitosis

Crncec

Hochegger

2019

FEBS Letters

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Entry into mitosis is triggered by the activation of cyclin‐dependent kinase 1 (Cdk1). This simple reaction rapidly and irreversibly sets the cell up for division. Even though the core step in triggering mitosis is so simple, the regulation of this cellular switch is highly complex, involving a large number of interconnected signalling cascades. We do have a detailed knowledge of most of the components of this network, but only a poor understanding of how they work together to create a precise and robust system that ensures that mitosis is triggered at the right time and in an orderly fashion. In this review, we will give an overview of the literature that describes the Cdk1 activation network and then address questions relating to the systems biology of this switch. How is the timing of the trigger controlled? How is mitosis insulated from interphase? What determines the sequence of events, following the initial trigger of Cdk1 activation? Which elements ensure robustness in the timing and execution of the switch? How has this system been adapted to the high levels of replication stress in cancer cells?

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“…69 Similar to our group, Rogers et al also showed that MASTL overexpression leads to significant disruption to the members of the Wnt-signaling pathway, including increased phosphorylation of β-catenin and mislocalization of E-cadherin. 23,25 However, the mechanism for MASTL regulation of GSK3β/Wnt signaling is still poorly understood and should be investigated in future studies. Overall, the above studies represent an alluring possibility that MASTL may have other substrates beyond ENSA and regulation of PP2A-B55.…”

Section: Cellular Transformation and Oncogenic Signaling Pathwaysmentioning

confidence: 99%

“…[17][18][19][20] The role of MASTL in regulating mitosis is now well-defined. [20][21][22] Also, a key role of MASTL in oncogenesis has recently been proposed in different cancer types, [23][24][25][26] however, details of the underlying mechanism/s and/or factors regulating MASTL expression/ activity during cancer progression remain unclear and needs detailed molecular investigation. In the light of the critical role of MASTL in cancer progression and unclear knowledge of its cancer promoting role and regulation, we present this review article that summarizes the knowledge from the recent publications regarding the role of MASTL deregulation in cancer progression, mechanism/s by which MASTL promotes tumorigenesis and its efficacy as a novel anticancer therapeutic target.…”

mentioning

confidence: 99%

MASTL: A novel therapeutic target for Cancer Malignancy

2020

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Targeting mitotic kinases is an emerging anticancer approach with promising preclinical outcomes. Microtubule‐associated serine/threonine kinase like (MASTL), also known as Greatwall (Gwl), is an important mitotic kinase that regulates mitotic progression of normal or transformed cells by blocking the activity of tumor suppressor protein phosphatase 2A (PP2A). MASTL upregulation has now been detected in multiple cancer types and associated with aggressive clinicopathological features. Apart, an aberrant MASTL activity has been implicated in oncogenic transformation through the development of chromosomal instability and alteration of key oncogenic signaling pathways. In this regard, recent publications have revealed potential role of MASTL in the regulation of AKT/mTOR and Wnt/β‐catenin signaling pathways, which may be independent of its regulation of PP2A‐B55 (PP2A holoenzyme containing a B55‐family regulatory subunit). Taken together, MASTL kinase has emerged as a novel target for cancer therapeutics, and hence development of small molecule inhibitors of MASTL may significantly improve the clinical outcomes of cancer patients. In this article, we review the role of MASTL in cancer progression and the current gaps in this knowledge. We also discuss potential efficacy of MASTL expression for cancer diagnosis and therapy.

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The Oncogenic Functions of MASTL Kinase

Cited by 32 publications

References 83 publications

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Triggering mitosis

MASTL: A novel therapeutic target for Cancer Malignancy

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