The DeMSTification of Mammalian Ste20 Kinases

Radu, Maria; Chernoff, Jonathan

doi:10.1016/j.cub.2009.04.022

Cited by 74 publications

(83 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5). It is likely that STS-induced apoptosis and apoptosis induced by inhibition of phosphatases do not operate through the Hippo pathway targeting YAP but rather involve other MST kinaseengaged pathways such as phosphorylation of histone H2B or phosphorylation of FOXO3 (19). Likewise, the data do not exclude the possibility that RASSF1A/MST signaling to YAP is crucial under conditions when the Hippo pathway is activated by more physiological stimuli, such as death receptor stimulation (28 -30).…”

Section: Rassf1a-associated Mst1 and Mst2 Kinasesmentioning

confidence: 62%

“…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 have also been reported to induce MST1/2 kinase activity, including Fas ligand, TNF␣, H 2 O 2 , serum starvation, and UV irradiation (19), but not cytokines, growth factors, protein synthesis inhibitors, DNA-damaging agents, protein denaturants, and forskolin (21). MST1 and MST2 share 78% identity and contain an N-terminal catalytic domain and a C-terminal SARAH (Salvador-Rassf-Hippo) domain known to be involved in homo-and heterodimerization reactions (22).…”

mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Guo

Zhang

Pfeifer

2011

Journal of Biological Chemistry

103

View full text Add to dashboard Cite

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...

show abstract

Section: Rassf1a-associated Mst1 and Mst2 Kinasesmentioning

confidence: 62%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Guo

Zhang

Pfeifer

2011

Journal of Biological Chemistry

103

View full text Add to dashboard Cite

show abstract

“…There are two mammalian MST genes, MST1 and MST2, which are almost identical in their kinase domains and exhibit a high degree of homology throughout the proteins (2). Although MST1 is known to activate apoptosis in cell cultures (3,4), MST1-knockout mice showed only a mild phenotype in T cell physiology (5,6).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of SAV1 by mammalian ste20-like kinase promotes cell death

Park

Lee

2011

BMB Reports

View full text Add to dashboard Cite

The mammalian ste20-like kinase (MST) pathway is important in the regulation of apoptosis and cell cycle and emerges as a novel tumor suppressor pathway. MST-induced phosphorylation of Salvador homolog 1 (SAV1), which is a scaffold protein, has not been evaluated in detail. We performed a mass spectrometric analysis of the SAV1 protein that was co-expressed with MST2. Phosphorylation was detected at Thr-26, Ser-27, Ser-36 and Ser-269. Although single or double mutations had little effects, the mutation of all four residues in SAV1 to Ala (SAV1-4A) had inhibitory effects on the MST pathway. MST2-mediated induction of SAV1-4A protein levels, SAV1-4A interaction with MST2 and the self-dimerization of SAV1-4A were weaker compared to those of wild-type SAV1. SAV1-4A inhibited MST2-and K-RasG12V-induced cell death of MCF7 cells. These results suggest that MST-mediated phosphorylation of four residues within SAV1 may be important in the induction of cell death by the MST pathway. [BMB reports 2011; 44(9): 584-589]

show abstract

“…The orthologs of Hippo and Warts are the proapoptotic MST kinases (12) and the proapoptotic LATS kinases (13). The human ortholog of Salvador is also referred to as Salvador.…”

mentioning

confidence: 99%

Salvador Protein Is a Tumor Suppressor Effector of RASSF1A with Hippo Pathway-independent Functions

Donninger

Allen²,

Henson

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

The RASSF1A tumor suppressor binds and activates proapoptotic MST kinases. The Salvador adaptor protein couples MST kinases to the LATS kinases to form the hippo pathway. Upon activation by RASSF1A, LATS1 phosphorylates the transcriptional regulator YAP, which binds to p73 and activates its proapoptotic effects. However, although serving as an adaptor for MST and LATS, Salvador can also bind RASSF1A. The functional role of the RASSF1A/Salvador interaction is unclear. Although Salvador is a novel tumor suppressor in Drosophila and mice, its role in human systems remains largely unknown. Here we show that Salvador promotes apoptosis in human cells and that Salvador inactivation deregulates the cell cycle and enhances the transformed phenotype. Moreover, we show that although the salvador gene is seldom mutated or epigenetically inactivated in human cancers, it is frequently down-regulated posttranscriptionally. Surprisingly, we also find that although RASSF1A requires the presence of Salvador for full apoptotic activity and to activate p73, this effect does not require a direct interaction of RASSF1A with MST kinases or the activation of the hippo pathway. Thus, we confirm a role for Salvador as a human tumor suppressor and RASSF1A effector and show that Salvador allows RASSF1A to modulate p73 independently of the hippo pathway.

show abstract

The DeMSTification of Mammalian Ste20 Kinases

Cited by 74 publications

References 49 publications

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

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

Phosphorylation of SAV1 by mammalian ste20-like kinase promotes cell death

Salvador Protein Is a Tumor Suppressor Effector of RASSF1A with Hippo Pathway-independent Functions

Contact Info

Product

Resources

About