MST, a Physiological Caspase Substrate, Highly Sensitizes Apoptosis Both Upstream and Downstream of Caspase Activation

Lee, Kyung-Kwon; Ohyama, Takahiro; Yajima, Nobuyuki; Tsubuki, Satoshi; Yonehara, Shin

doi:10.1074/jbc.m005109200

Cited by 185 publications

(233 citation statements)

References 46 publications

(60 reference statements)

Supporting

Mentioning

223

Contrasting

Order By: Relevance

“…Murine brain lysate was incubated with active-site titrated recombinant CASP3, 6 or 7, and STK3 cleavage was assessed. As expected, CASP3 and CASP6 cleave STK3 (Riechers et al 2016;Lee et al 2001). However, we also observed cleavage by CASP7 and noted that the caspases do not cleave STK3 with the same efficacy and do not produce the same fragment sizes.…”

Section: Differential Cleavage Of Stk3 By Casp3 6 Andsupporting

confidence: 81%

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

Lessard‐Beaudoin

Laroche

Loudghi

et al. 2016

Neurobiology of Aging

View full text Add to dashboard Cite

Caspases and their substrates are key mediators of apoptosis and strongly implicated in various physiological processes. As the STK family is involved in apoptosis, and STK3 is a recently identified caspase-6 substrate, we assessed the expression and cleavage of STK3 in murine peripheral organs and brain regions during the aging process. We also assessed caspase-3, -6, -7 and -8 expression and activity in order to delineate potential mechanism(s) underlying the generation of the STK3 fragments observed, and their relation to the apoptotic pathway. We demonstrate for the first time the cleavage of STK3 by caspase-7 and show that STK3 protein levels globally increase throughout the organism with age. In contrast, caspase-3, -6, -7 and -8 expression and activity vary significantly amongst the different organs analyzed suggesting differential effects of aging on the apoptotic mechanism and/or non-apoptotic functions of caspases throughout the organism. These results further our understanding of the role of caspases and their substrates in the normal aging process and highlight a potential role for STK3 in neurodegeneration.3

show abstract

Section: Differential Cleavage Of Stk3 By Casp3 6 Andsupporting

confidence: 81%

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

Lessard‐Beaudoin

Laroche

Loudghi

et al. 2016

Neurobiology of Aging

View full text Add to dashboard Cite

show abstract

“…1,[8][9][10] Cellular localization of Mst1 is also regulated by caspase-mediated cleavage as well as threonine phosphorylation. 7,8,11 Under resting conditions, Mst1 is localized predominantly in the cytoplasm but cleavage of Mst1 by caspases or phosphorylation in its activation loop lead to Mst1 translocation to the nucleus. 7,8,11 Nuclear retention of Mst1 results in chromatin condensation and DNA fragmentation indicating that nuclear entry of Mst1 may be important in its pro-apoptotic function.…”

mentioning

confidence: 99%

“…7,8,11 Under resting conditions, Mst1 is localized predominantly in the cytoplasm but cleavage of Mst1 by caspases or phosphorylation in its activation loop lead to Mst1 translocation to the nucleus. 7,8,11 Nuclear retention of Mst1 results in chromatin condensation and DNA fragmentation indicating that nuclear entry of Mst1 may be important in its pro-apoptotic function. 11,12 Extensive studies to identify potential Mst1 substrates in the nucleus have led to identification of Histone H2B as a physiologic substrate for the catalytic domain of Mst1, the phosphorylation of which leads to chromatin condensation and apoptosis.…”

mentioning

confidence: 99%

“…7,8,11 Nuclear retention of Mst1 results in chromatin condensation and DNA fragmentation indicating that nuclear entry of Mst1 may be important in its pro-apoptotic function. 11,12 Extensive studies to identify potential Mst1 substrates in the nucleus have led to identification of Histone H2B as a physiologic substrate for the catalytic domain of Mst1, the phosphorylation of which leads to chromatin condensation and apoptosis. 13 Based on its proposed function in apoptosis, Mst1 might play a tumor suppressor role in human cancers as has been suggested for its Drosophila homologs.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer

et al. 2007

View full text Add to dashboard Cite

Mammalian Sterile20-like kinase 1 (Mst1) is a member of the yeast Ste20-related kinase family known to be involved in the process of apoptosis initiated by a variety of stimuli. The aim of this study was to determine the prognostic significance of Mst1 expression in colorectal cancer. A series of 1197 mismatch-repair-proficient colorectal cancers retrieved from a tissue microarray were randomized into two study groups. On the first group (n ¼ 599) receiver operating characteristic curves were used to determine the most clinically useful cutoffs to describe Mst1 expression with respect to T stage, N stage, tumor grade, vascular invasion and overall survival. The association of Mst1 expression and each outcome was immunohistochemically evaluated on the second study group (n ¼ 598) as well as on a third study group comprising 141 mismatch-repair-deficient colorectal cancers. A univariate analysis in the second study group showed that loss of cytoplasmic Mst1 was associated with higher T stage (P ¼ 0.001), higher N stage (P ¼ 0.029), vascular invasion (P ¼ 0.017) and overall survival (P ¼ 0.014). Nuclear Mst1 expression was not significantly associated with N stage, T stage or vascular invasion but was associated with tumor grade. In mismatch-repair-deficient colorectal cancers, loss of cytoplasmic Mst1 was associated with higher N stage (P ¼ 0.019) and shortened survival (P ¼ 0.0001). In a multivariate analysis, loss of cytoplasmic Mst1 was an independent adverse prognostic factor in this group of patients. Methylation analysis on 32 cases showed that the loss of cytoplasmic Mst1 expression is not likely due to promoter methylation. In summary, loss of cytoplasmic Mst1 expression is a marker of tumor progression in mismatchrepair-proficient as well as mismatch-repair-deficient colorectal cancers. These results are suggestive of a tumor suppressor role for Mst1 in human colorectal cancer.

show abstract

“…We therefore examined, whether overexpression of plasma membrane-based A-Raf preserved this function, by activating MST2 using etoposide. 16,50 Although overexpression of wt A-Raf inhibited MST2 activation ( Figure 2e) and reduced apoptosis induced by etoposide (Figure 2f), A-Raf-CAAX could neither prevent activation of MST2 nor etoposidetriggered apoptosis (Figures 2e and f). In addition, expression of neither wt nor membrane-targeted A-Raf influenced proliferation (Supplementary Figure S2A Figure S2E), indicating that the localization-specific regulation by A-Raf selectively affects the MST2 but not the ERK pathway.…”

Section: Resultsmentioning

confidence: 98%

Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation

et al. 2016

View full text Add to dashboard Cite

A-Raf belongs to the family of oncogenic Raf kinases that are involved in mitogenic signaling by activating the MEK-ERK pathway. Low kinase activity of A-Raf toward MEK suggested that A-Raf might have alternative functions. We recently identified A-Raf as a potent inhibitor of the proapoptotic mammalian sterile 20-like kinase (MST2) tumor suppressor pathway in several cancer entities including head and neck, colon, and breast. Independent of kinase activity, A-Raf binds to MST2 thereby efficiently inhibiting apoptosis. Here, we show that the interaction of A-Raf with the MST2 pathway is regulated by subcellular compartmentalization. Although in proliferating normal cells and tumor cells A-Raf localizes to the mitochondria, differentiated non-carcinogenic cells of head and neck epithelia, which express A-Raf at the plasma membrane. The constitutive or induced re-localization of A-Raf to the plasma membrane compromises its ability to efficiently sequester and inactivate MST2, thus rendering cells susceptible to apoptosis. Physiologically, A-Raf re-localizes to the plasma membrane upon epithelial differentiation in vivo. This re-distribution is regulated by the scaffold protein kinase suppressor of Ras 2 (KSR2). Downregulation of KSR2 during mammary epithelial cell differentiation or siRNA-mediated knockdown re-localizes A-Raf to the plasma membrane causing the release of MST2. By using the MCF7 cell differentiation system, we could demonstrate that overexpression of A-Raf in MCF7 cells, which induces differentiation. Our findings offer a new paradigm to understand how differential localization of Raf complexes affects diverse signaling functions in normal cells and carcinomas. A-Raf is a member of the Raf family of serine-threonine protein kinases, which comprises A-Raf, B-Raf, and Raf-1. Raf kinases are at the apex of the three-tiered Raf/MEK/ extracellular signal-regulated kinase (ERK) (mitogen-activated protein kinase (MAPK)) pathway regulating fundamental cellular functions, including differentiation, transformation, apoptosis, proliferation, and metabolism. 1,2 Activation of Ras GTPases at the cell membrane initiates Raf kinase activation and sequential phosphorylation and activation of the serinethreonine kinases MEK1/2 and ERK1/2. 3,4 In comparison to Raf-1 and B-Raf, A-Raf is only weakly activated by oncogenic H-Ras and Src 5 and is a poor MEK kinase, 5-8 which is due to unique non-conserved amino acid substitutions in the N-region. 9 Only recently, the first somatic oncogenic mutations of A-Raf were identified in lung adenocarcinomas 10 and Langerhans cell histiocytosis. 11,12 We recently showed that A-Raf and Raf-1, independent of their kinase activity, bind the proapoptotic mammalian sterile 20-like kinase (MST2) thereby suppressing MST2 activation and MST2-induced apoptosis. 13-17 MST2 employs several mechanisms to induce apoptosis including the transcriptional induction of PUMA, 14 a BH3 domain protein that causes mitochondrial depolarization and subsequent cell death. 18 Although Raf-1 counteracts MS...

show abstract

MST, a Physiological Caspase Substrate, Highly Sensitizes Apoptosis Both Upstream and Downstream of Caspase Activation

Cited by 185 publications

References 46 publications

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer

Differential localization of A-Raf regulates MST2-mediated apoptosis during epithelial differentiation

Contact Info

Product

Resources

About