In vivo inactivation of MASTL kinase results in thrombocytopenia

Johnson, H. Jan; Gandhi, Manish J.; Shafizadeh, Ebrahim; Langer, Nathaniel B.; Pierce, Eric T.; Paw, Barry H.; Gilligan, Diana M.; Drachman, Jonathan G.

doi:10.1016/j.exphem.2009.05.005

Cited by 31 publications

(21 citation statements)

References 21 publications

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“…19 A functional genomic screen found MASTL as a potential determinant of taxol sensitivity and showed that depletion of MASTL induces polyploidy in the colon cancer cell line HCT-116. 21 Furthermore, MASTL may help to prevent thrombocytopenia (a low thrombocyte count) 22,23 and is suggested to control endocytic transport. 24 However, no function for MASTL in the cell cycle had been described.…”

Section: Resultsmentioning

confidence: 99%

MASTL is the human ortholog of Greatwall kinase that facilitates mitotic entry, anaphase and cytokinesis

Voets

Wolthuis²

2010

Cell Cycle

125

134

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Section: Resultsmentioning

confidence: 99%

MASTL is the human ortholog of Greatwall kinase that facilitates mitotic entry, anaphase and cytokinesis

Voets

Wolthuis²

2010

Cell Cycle

125

134

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“…Both of these publications focus on the role of MAST-L in autosomal-dominant thrombocytopenia, showing that a single-point mutation (E167D) in the N-terminal kinase domain correlates with this syndrome (12), and transient knockdown in zebrafish results in a reduction of circulating thrombocytes (13).…”

mentioning

confidence: 99%

Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance

Burgess

Vigneron

Brioudes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

640

605

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Here we show that the functional human ortholog of Greatwall protein kinase (Gwl) is the microtubule-associated serine/threonine kinase-like protein, MAST-L. This kinase promotes mitotic entry and maintenance in human cells by inhibiting protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates cyclin B-Cdc2 substrates. The complete depletion of Gwl by siRNA arrests human cells in G2. When the levels of this kinase are only partially depleted, however, cells enter into mitosis with multiple defects and fail to inactivate the spindle assembly checkpoint (SAC). The ability of cells to remain arrested in mitosis by the SAC appears to be directly proportional to the amount of Gwl remaining. Thus, when Gwl is only slightly reduced, cells arrest at prometaphase. More complete depletion correlates with the premature dephosphorylation of cyclin B-Cdc2 substrates, inactivation of the SAC, and subsequent exit from mitosis with severe cytokinesis defects. These phenotypes appear to be mediated by PP2A, as they could be rescued by either a double Gwl/PP2A knockdown or by the inhibition of this phosphatase with okadaic acid. These results suggest that the balance between cyclin B-Cdc2 and PP2A must be tightly regulated for correct mitotic entry and exit and that Gwl is crucial for mediating this regulation in somatic human cells.spindle assembly checkpoint | cell cycle | phosphatase | kinase | slippage I n eukaryotic cells, the mitotic state is maintained by the mitotic kinase cyclin B-Cdc2. Historically, mitotic entry and exit was thought to be the direct consequence of cyclin B-Cdc2 activation and inactivation, respectively (1). Recent results have expanded this model to include phosphatases (2). Specifically, recent evidence indicates that protein phosphatase 2A (PP2A) is responsible for dephosphorylation of cyclin B-Cdc2 substrates and that the regulation of this dephosphorylation is required in mitotic entry and exit (3). This finding suggests a previously unexplored model in which the balance between cyclin B-Cdc2 and PP2A controls mitotic entry and exit. Thus, during G2 PP2A activity is high and cyclin B-Cdc2 activity low, thereby preventing phosphorylation of mitotic substrates, whereas at mitotic entry the balance flips, allowing entry into mitosis. The mechanisms controlling cyclin B-Cdc2 activity have been largely described (4). Briefly, cyclin B-Cdc2 is inhibited during G2 by inhibitory phosphorylations on threonine 14 and tyrosine 15 by Wee1 and Myt1 kinases. Upon mitotic entry, these are removed by the Cdc25 phosphatase (4). Finally, at mitotic exit cyclin B-Cdc2 is inhibited by the ubiquitin-dependent degradation of its regulatory subunit cyclin B (5). Unlike cyclin B-Cdc2 regulation, very little is known about the mechanisms controlling PP2A activity during mitosis, and therefore our understanding of G2 and mitosis is incomplete.Recently, Greatwall (Gwl), a unique critical mitotic regulator, has been discovered in Drosophila (6, 7). It is a member of the AGC family of serine/threonine kinases that ph...

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“…After localization of a locus on human chromosome 10p, the microtubule-associated serine/threonine-like kinase (MASTL) gene was identified as a candidate. Knockdown of the zebrafish ortholog with MOs resulted in reduction of circulating thrombocytes, as well as decreased expression of itga2b and mpl , providing supportive evidence [50]. MO knockdown in zebrafish also reinforced the discoveries of NBEAL2 and RBM8A as the affected genes in the gray platelet and thrombocytopenia with absent radii syndromes, respectively [51,52].…”

Section: Dissection Of Human Coagulation and Associated Disorders Usimentioning

confidence: 81%

Zebrafish as a model system for the study of hemostasis and thrombosis

Weyand

Shavit

2014

Current Opinion in Hematology

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Purpose of review Although the zebrafish has been established as a research tool over the past 2–3 decades, in hematology it has primarily been used to investigate areas distinct from coagulation. Advantages of this vertebrate model include high fecundity, rapid and external development, and conservation of virtually all clotting factors in the zebrafish genomic sequence. Here we summarize the growing application of this technology to the study of hemostasis and thrombosis. Recent findings Loss of function studies have demonstrated conservation of function for a number of zebrafish coagulation factors. These include positive and negative regulators of coagulation, as well as key components of the thrombus itself, such as von Willebrand factor, fibrinogen, and thrombocytes. Such analyses have also been leveraged to aid in the understanding of human variation and disease, as well as perform in vivo structure/function experiments. Summary The zebrafish is an organism that lends itself to a number of unique and powerful approaches not possible in mammals. This review demonstrates that there is a high degree of genetic and functional conservation of coagulation, portending future insights into hemostasis and thrombosis through use of this model.

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In vivo inactivation of MASTL kinase results in thrombocytopenia

Cited by 31 publications

References 21 publications

MASTL is the human ortholog of Greatwall kinase that facilitates mitotic entry, anaphase and cytokinesis

MASTL is the human ortholog of Greatwall kinase that facilitates mitotic entry, anaphase and cytokinesis

Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance

Zebrafish as a model system for the study of hemostasis and thrombosis

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