Proteolytic activation of MST/Krs, STE20-related protein kinase, by caspase during apoptosis

Lee, Kyung-Kwon; Murakawa, Masao; Nishida, Eisuke; Tsubuki, Satoshi; Kawashima, Seiichi; Sakamaki, Kazuhiro; Yonehara, Shin

doi:10.1038/sj.onc.1201840

Cited by 123 publications

(144 citation statements)

References 23 publications

(26 reference statements)

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“…In this respect, several kinases, including MEKK1, 60 MST, 61 and PAK2, 62 have been reported to be cleaved by caspases, resulting in their activation. Under the conditions in which NF-kB activation is impaired, TNFa stimulation induces both caspase-dependent apoptosis and ROS-dependent necrosis.…”

Section: Opening Of This Pore Results In Massive Loss Of Ions and Metmentioning

confidence: 99%

Reactive oxygen species mediate crosstalk between NF-κB and JNK

et al. 2005

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The activation of NF-jB inhibits apoptosis via a mechanism involving upregulation of various antiapoptotic genes, such as cellular FLICE-inhibitory protein (c-FLIP), Bcl-x L , A1/Bfl-1, and X chromosome-liked inhibitor of apoptosis (XIAP). In contrast, the activation of c-Jun N-terminal kinase (JNK) promotes apoptosis in a manner that is dependent on the cell type and the context of the stimulus. Recent studies have indicated that one of the antiapoptotic functions of NF-jB is to downregulate JNK activation. Further studies have also revealed that NF-jB inhibits JNK activation by suppressing accumulation of reactive oxygen species (ROS). In this review, we will focus on the signaling crosstalk between the NF-jB and JNK cascades via ROS.

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Section: Opening Of This Pore Results In Massive Loss Of Ions and Metmentioning

confidence: 99%

Reactive oxygen species mediate crosstalk between NF-κB and JNK

et al. 2005

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“…At the ®nal stage of our studies, two groups using a di erent approach showed the importance of MST/Krs in apoptosis. Lee et al (1998) reported that one of the substrates of caspase-3 is MST/Krs, and Graves et al (1998) reported that active MST1 activates MKK7, an upstream activator of JNK. Our observation in MT-21-induced apoptosis is consistent with their observations.…”

Section: Discussionmentioning

confidence: 99%

Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis

1999

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Fas is a well characterized apoptosis-inducing factor. One of our synthetic compounds, MT-21, induced apoptosis in human leukemia HL-60 cells similar to Fas. MT-21 activated caspase-3, an important cysteine aspartic protease for apoptosis induction. MT-21 also activated c-Jun-NH 2 -terminal kinase (JNK), a member of mitogen activated protein kinase (MAPK) superfamily that is involved in the regulation of cell growth, di erentiation and cell death. Moreover, MT-21 treatment resulted in the activation of a 36 kDa kinase which uses myelin basic protein (MBP) as a substrate. However, MAPK and p38 were not activated by treatment with MT-21. The 36 kDa MBP kinase was shown to be a proteolytic product derived from the Krs protein with a molecular weight of 60 kDa. The Krs protein is a Ser/Thr protein kinase whose activity is enhanced by digestion of its C-terminal regulatory domain by caspase-3. When a kinase-inactive mutant form of Krs protein was overexpressed in HL-60 cells, JNK activation and apoptosis induction by MT-21 were suppressed. Furthermore, overexpression of dominant negative c-Jun also suppressed apoptosis induction by MT-21. These ®ndings indicate that MT-21 induces apoptosis by the activation of JNK via the Krs protein, which is activated by caspase cleavage.

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“…It is likely that a kinase other than MEKK1 might also contribute to prolonged JNK and ERK activation. Indeed, several kinases including p21-activated kinase2 and mammalian Sterile20-like kinases have been shown to be cleaved by caspases, and activate the JNK pathway (Lee et al, 1998;Rudel et al, 1998). In addition, given that ROS activate MAPKKKs including c-FLIP suppresses caspase-dependent JNK and ROS A Nakajima et al apoptosis signal-regulating kinase (ASK)1 (Saitoh et al, 1998), ASK1 might also contribute to prolonged JNK activation in c-FLIP knockdown cells.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells

et al. 2007

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Nuclear factor-kappa B (NF-jB) inhibits cell death through suppression of the caspase cascade, the c-Jun N-terminal kinase (JNK) pathway, and reactive oxygen species (ROS) accumulation. To suppress this antiapoptotic function of NF-jB might be a promising strategy to increase susceptibility of tumor cells to stress-induced cell death. We have recently shown that tumor necrosis factor (TNF)a induces caspase-dependent and -independent JNK activation and ROS accumulation in cellular FLICEinhibitory protein (c-Flip) À/À murine embryonic fibroblasts (MEFs). To apply this observation to tumor therapy, we knocked down c-FLIP by RNA interference in various tumor cells. Consistent with the results using c-Flip À/À MEFs, we found that TNFa stimulation induced caspase-dependent prolonged JNK activation and ROS accumulation, followed by apoptotic and necrotic cell death in various tumor cells. Furthermore, TNFa and Fas induced the cleavage of mitogen-activated protein kinase/ ERK kinase kinase (MEKK)1, resulting in generation of a constitutive active form of MEKK1 leading to JNK activation in c-FLIP knockdown cells. Given that ROS accumulation and necrotic cell death enhance inflammation followed by compensatory proliferation of tumor cells, selective suppression of caspase-dependent ROS accumulation will be an alternative strategy to protect cells from ROS-dependent DNA damage and compensatory tumor progression.

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Proteolytic activation of MST/Krs, STE20-related protein kinase, by caspase during apoptosis

Cited by 123 publications

References 23 publications

Reactive oxygen species mediate crosstalk between NF-κB and JNK

Reactive oxygen species mediate crosstalk between NF-κB and JNK

Requirement of protein kinase (Krs/MST) activation for MT-21-induced apoptosis

Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells

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