A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct

Ocasio, Cory A.; Rajasekaran, Mohan B.; Walker, Sarah; Grand, Darren Le; Spencer, John; Pearl, Frances M. G.; Ward, Simon E.; Savic, Velibor; Pearl, Laurence H.; Hochegger, Helfrid; Oliver, Antony W.

doi:10.18632/oncotarget.11511

Cited by 30 publications

(37 citation statements)

References 42 publications

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“…The ability of MASTL knockdown to delay both primary tumour growth and prevent metastasis suggests that inhibiting MASTL may be a valid therapeutic strategy for the treatment of breast cancer, which is also supported by another manuscript that was published during the revision of our paper [ 16 ]. Excitingly, a first-generation small molecule inhibitor for MASTL was recently identified [ 45 ], and the utility of second-generation inhibitors as targeted chemotherapeutics will be of great interest. In summary, we confirm previous reports that MASTL overexpression disrupts PI3K/ATK/mTOR signalling, which over-comes contact inhibition, drives a partial EMT phenotype allowing uncontrolled proliferation.…”

Section: Discussionmentioning

confidence: 99%

MASTL overexpression promotes chromosome instability and metastasis in breast cancer

et al. 2018

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MASTL kinase is essential for correct progression through mitosis, with loss of MASTL causing chromosome segregation errors, mitotic collapse and failure of cytokinesis. However, in cancer MASTL is most commonly amplified and overexpressed. This correlates with increased chromosome instability in breast cancer and poor patient survival in breast, ovarian and lung cancer. Global phosphoproteomic analysis of immortalised breast MCF10A cells engineered to overexpressed MASTL revealed disruption to desmosomes, actin cytoskeleton, PI3K/AKT/mTOR and p38 stress kinase signalling pathways. Notably, these pathways were also disrupted in patient samples that overexpress MASTL. In MCF10A cells, these alterations corresponded with a loss of contact inhibition and partial epithelial–mesenchymal transition, which disrupted migration and allowed cells to proliferate uncontrollably in 3D culture. Furthermore, MASTL overexpression increased aberrant mitotic divisions resulting in increased micronuclei formation. Mathematical modelling indicated that this delay was due to continued inhibition of PP2A-B55, which delayed timely mitotic exit. This corresponded with an increase in DNA damage and delayed transit through interphase. There were no significant alterations to replication kinetics upon MASTL overexpression, however, inhibition of p38 kinase rescued the interphase delay, suggesting the delay was a G2 DNA damage checkpoint response. Importantly, knockdown of MASTL, reduced cell proliferation, prevented invasion and metastasis of MDA-MB-231 breast cancer cells both in vitro and in vivo, indicating the potential of future therapies that target MASTL. Taken together, these results suggest that MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival.

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Section: Discussionmentioning

confidence: 99%

MASTL overexpression promotes chromosome instability and metastasis in breast cancer

et al. 2018

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“…It is of considerable interest that similar or even somewhat higher concentrations of these components are found in human platelets (1.73 µM all PP2A B subunits, 1.7 µM ENSA-ARPP19, Table S2). There is important evidence that the family of regulatory B subunits defines special properties of PP2A protein phosphatases, including ENSA/ARPP19 inhibitory effects, PP2A substrate specificity, interaction with additional proteins and subcellular localization [26,[64][65][66][67]. Interestingly, mammalian cells have a much higher number of B subunit genes than lower eukaryotes [68].…”

Section: Ser-phosphorylated Arpp19 Is Both a Substrate For And Inhibimentioning

confidence: 99%

The Cell Cycle Checkpoint System MAST(L)-ENSA/ARPP19-PP2A is Targeted by cAMP/PKA and cGMP/PKG in Anucleate Human Platelets

Kumm

Pagel

Gambaryan

et al. 2020

Cells

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The cell cycle is controlled by microtubule-associated serine/threonine kinase-like (MASTL), which phosphorylates the cAMP-regulated phosphoproteins 19 (ARPP19) at S62 and 19e/α-endosulfine (ENSA) at S67and converts them into protein phosphatase 2A (PP2A) inhibitors. Based on initial proteomic data, we hypothesized that the MASTL-ENSA/ARPP19-PP2A pathway, unknown until now in platelets, is regulated and functional in these anucleate cells. We detected ENSA, ARPP19 and various PP2A subunits (including seven different PP2A B-subunits) in proteomic studies of human platelets. ENSA-S109/ARPP19–S104 were efficiently phosphorylated in platelets treated with cAMP- (iloprost) and cGMP-elevating (NO donors/riociguat) agents. ENSA-S67/ARPP19-S62 phosphorylations increased following PP2A inhibition by okadaic acid (OA) in intact and lysed platelets indicating the presence of MASTL or a related protein kinase in human platelets. These data were validated with recombinant ENSA/ARPP19 and phospho-mutants using recombinant MASTL, protein kinase A and G. Both ARPP19 phosphorylation sites S62/S104 were dephosphorylated by platelet PP2A, but only S62-phosphorylated ARPP19 acted as PP2A inhibitor. Low-dose OA treatment of platelets caused PP2A inhibition, diminished thrombin-stimulated platelet aggregation and increased phosphorylation of distinct sites of VASP, Akt, p38 and ERK1/2 MAP kinases. In summary, our data establish the entire MASTL(like)–ENSA/ARPP19–PP2A pathway in human platelets and important interactions with the PKA, MAPK and PI3K/Akt systems.

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“…In summary, it is clear that under specific conditions MASTL is a highly promising target for several cancers including breast, lung, colon and ovarian. With the recent identification of a first-generation MASTL inhibitor ( Ocasio et al, 2016 ), the potential for a future therapeutic breakthrough is looking promising and exciting.…”

Section: Targeting Mastl In Cancermentioning

confidence: 99%

The Oncogenic Functions of MASTL Kinase

Marzec

Burgess

2018

Front. Cell Dev. Biol.

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MASTL kinase is a master regulator of mitosis, essential for ensuring that mitotic substrate phosphorylation is correctly maintained. It achieves this through the phosphorylation of alpha-endosulfine and subsequent inhibition of the tumor suppressor PP2A-B55 phosphatase. In recent years MASTL has also emerged as a novel oncogenic kinase that is upregulated in a number of cancer types, correlating with chromosome instability and poor patient survival. While the chromosome instability is likely directly linked to MASTL’s control of mitotic phosphorylation, several new studies indicated that MASTL has additional effects outside of mitosis and beyond regulation of PP2A-B55. These include control of normal DNA replication timing, and regulation of AKT/mTOR and Wnt/β-catenin oncogenic kinase signaling. In this review, we will examine the phenotypes and mechanisms for how MASTL, ENSA, and PP2A-B55 deregulation drives tumor progression and metastasis. Finally, we will explore the rationale for the future development of MASTL inhibitors as new cancer therapeutics.

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A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct

Cited by 30 publications

References 42 publications

MASTL overexpression promotes chromosome instability and metastasis in breast cancer

MASTL overexpression promotes chromosome instability and metastasis in breast cancer

The Cell Cycle Checkpoint System MAST(L)-ENSA/ARPP19-PP2A is Targeted by cAMP/PKA and cGMP/PKG in Anucleate Human Platelets

The Oncogenic Functions of MASTL Kinase

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