MOBKL1A/MOBKL1B Phosphorylation by MST1 and MST2 Inhibits Cell Proliferation

Praskova, Maria; Xia, Fan; Avruch, Joseph

doi:10.1016/j.cub.2008.02.006

Cited by 371 publications

(443 citation statements)

References 34 publications

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“…First, we used myelin basic protein as substrate for assaying MST1 kinase activity, but found only a weak signal (data not shown). Therefore, we used a GST-fusion MOBKL1B protein, which was reported to be a good MST1 substrate (Praskova et al, 2008). We basically found similar results to those in the autophosphorylation analyses (Figure 2b), thus confirming MST1 activation by PRX-I.…”

Section: Resultssupporting

confidence: 80%

“…Having confirmed H 2 O 2 generation, we next examined PRX-I oligomer formation and found that cisplatin treatment could induce oligomers of both ectopically expressed PRX-I in COS-7 cells and endogenous PRX-I in U2OS cells (Figures 3b and c). We noticed that p53 levels significantly increased in U2OS cells upon cisplatin treatment (Figure 3c) as reported previously (Praskova et al, 2008). Therefore, we next examined whether p53 has any important role in PRX-I oligomer formation induced by cisplatin treatment.…”

Section: Cisplatin Induces Prx-i Oligomer Formation Through P53supporting

confidence: 85%

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Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

et al. 2011

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Mammalian Ste20-like kinase-1 (MST1) kinase mediates H 2 O 2 -induced cell death by anticancer drugs such as cisplatin in a p53-dependent manner. However, the mechanism underlying MST1 activation by H 2 O 2 remains unknown. Here we show that peroxiredoxin-I (PRX-I) is an essential intermediate in H 2 O 2 -induced MST1 activation and cisplatin-induced cell death through p53. Cell stimulation with H 2 O 2 resulted in PRX-I oxidation to form homo-oligomers and interaction with MST1, leading to MST1 autophosphorylation and augmentation of kinase activity. In addition, RNA interference knockdown experiments indicated that endogenous PRX-I is required for H 2 O 2 -induced MST1 activation. Live-cell imaging showed H 2 O 2 generation by cisplatin treatment, which likewise caused PRX-I oligomer formation, MST1 activation and cell death. Cisplatin-induced PRX-I oligomer formation was not observed in embryonic fibroblasts obtained from p53-knockout mice, confirming the importance of p53. Indeed, ectopic expression of p53 induced PRX-I oligomer formation and cell death, both of which were cancelled by the antioxidant NAC. Moreover, we succeeded in reconstituting H 2 O 2 -induced MST1 activation in vitro, using purified PRX-I and MST1 proteins. Collectively, our results show a novel PRX-I function to cause cell death in response to high levels of oxidative stress by activating MST1, which underlies the p53-dependent cytotoxicity caused by anticancer agents.

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Section: Resultssupporting

confidence: 80%

Section: Cisplatin Induces Prx-i Oligomer Formation Through P53supporting

confidence: 85%

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

et al. 2011

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“…For example, in contrast to findings from Drosophila, no evidence was found that mammalian merlin positively regulates mammalian MST2 (36). Of note, there are several reports that have linked the function of MST kinases to centrosome duplication (41), mitotic control (7,42,43), and lymphocyte trafficking (44). Thus, prevention of MST dephosphorylation by RASSF1A or perhaps by related RASSF family members may also play an important role in these pathways.…”

Section: Discussionmentioning

confidence: 94%

The Tumor Suppressor RASSF1A Prevents Dephosphorylation of the Mammalian STE20-like Kinases MST1 and MST2

Guo

Zhang

Pfeifer

2011

Journal of Biological Chemistry

103

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The RASSF1A tumor suppressor protein interacts with the pro-apoptotic mammalian STE20-like kinases MST1 and MST2 and induces their autophosphorylation and activation, but the mechanism of how RASSF1A activates MST1/2 is unclear. Okadaic acid treatment and PP2A knockdown promoted MST1/2 phosphorylation. Data from dephosphorylation assays and reduced activation of MST1/2 seen after RASSF1A depletion suggest that dephosphorylation of MST1/2 on Thr-183 and Thr-180 by PP2A is prevented by RASSF1A, shifting the balance of MST1/2 to the activated autophosphorylated form. In addition to preventing dephosphorylation, RASSF1A also stabilized the MST2 protein. Through binding to MST1/2, RASSF1A supports maintenance of MST1/2 phosphorylation, promoting an active state of the MST kinases and favoring induction of apoptosis. This is one of the first examples of a tumor suppressor acting as an inhibitor of a specific dephosphorylation pathway.The RASSF1A (Ras association domain family 1 isoform A) gene is localized on chromosome 3p21.3, in an area that likely harbors at least one important tumor suppressor gene (1, 2). RASSF1A is frequently silenced by promoter hypermethylation in many human tumors (3, 4). Rassf1a-targeted mice are prone to spontaneous and carcinogen-induced tumorigenesis (5, 6). The RASSF1A protein is involved in several growth regulatory and pro-apoptotic pathways. Recent work has shown that RASSF1A associates with components of the mammalian Hippo signaling network (7), an emerging pathway implicated in organ size control, restriction of cell proliferation, apoptosis, and tumor suppression (8 -10). RASSF1A interacts with the mammalian kinases MST1 and MST2, the orthologs of the Drosophila Hippo kinase, and activates MST1 and MST2 by promoting their autophosphorylation and phosphorylation of the downstream LATS1 kinase (7).The mammalian Sterile-20-like kinases MST1 (also known as STK4 and KRS2) and MST2 (also known as STK3 and KRS1) belong to the class II germinal center (Ser/Thr protein) kinases (11). MST1 and MST2 have recently been implicated as important tumor suppressors (12)(13)(14), suggesting that the RASSF-MST complexes may represent intriguing tumor-suppressing modules. Besides their potential role in promoting apoptosis through the Hippo pathway, MST1 and MST2 are implicated in several other pro-apoptotic processes. During induction of apoptosis, MST1 and MST2 can be activated, leading to phosphorylation of histone H2B and nuclear DNA fragmentation (15). In addition, the activation of JNK (Jun N-terminal kinase) signaling (16, 17) and phosphorylation of FOXO3 transcription factors (18) have also been associated with MST-induced apoptosis.The MST1 and MST2 kinases are regulated by several mechanisms, including phosphorylation, caspase cleavage, dimerization, and cofactors (19). They are activated in response to staurosporine (STS), 2 a potent protein kinase C inhibitor and apoptosis inducer, or the protein phosphatase inhibitor okadaic acid (20). Several other pro-apoptotic stimuli and stresses hav...

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“…The activation of Mst1/2 leads to phosphorylation and activation of their direct substrates, Lats1/2 (Chan et al, 2005). Mob1, which forms a complex with Lats1/2 (Chow et al, 2010), is also phosphorylated and activated by Mst1/2, resulting in enhanced interaction between Lats1/2 and Mob1 (Hirabayashi et al, 2008;Praskova et al, 2008). Similar to that in Drosophila, MST1/2/Sav1 and Lats1/2/Mob1 form a physical and functional core of the Hippo pathway.…”

Section: The Mammalian Hippo Pathwaymentioning

confidence: 94%

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

et al. 2012

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This pathway was first found to inhibit cell proliferation and promote apoptosis, therefore regulating cell number and organ size in both Drosophila and mammals. However, in several organs, disturbance of the pathway leads to specific expansion of the progenitor cell compartment and manipulation of the pathway in embryonic stem cells strongly affects their self-renewal and differentiation. In this review, we summarize current observations on roles of the Hippo pathway in different types of stem cells and discuss how these findings changed our view on the Hippo pathway in organ development and tumorigenesis.

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MOBKL1A/MOBKL1B Phosphorylation by MST1 and MST2 Inhibits Cell Proliferation

Abstract: These results establish that MST1 and MST2 are activated in mitosis and catalyze the mitotic phosphorylation of MOBKL1A/MOBKL1B. MOBKL1A/MOBKL1B phosphorylation, in turn, is sufficient to inhibit proliferation through actions at several points in the cell cycle.

Cited by 371 publications

References 34 publications

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

The Tumor Suppressor RASSF1A Prevents Dephosphorylation of the Mammalian STE20-like Kinases MST1 and MST2

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

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