hMOB3 Modulates MST1 Apoptotic Signaling and Supports Tumor Growth in Glioblastoma Multiforme

Tang, Fengyuan; Zhang, Lei; Xue, Gui-Rong; Hynx, Debby; Wang, Yuhua; Cron, Peter; Hundsrucker, Christian; Hergovich, Alexander; Frank, Stephan; Hemmings, Brian A.; Schmitz-Rohmer, Debora

doi:10.1158/0008-5472.can-13-3430

Cited by 20 publications

(28 citation statements)

References 47 publications

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“…In such context, the excessive MST4 and MOB4 can disturb the MST1-MOB1 complex by competitively pairing with MST1/MOB1. Consistent with this notion, MOB3A/B/C was reported to negatively regulate MST1 in glioblastoma multiforme cells through direct MOB3A/B/C-MST1 tethering (16).…”

Section: Discussionsupporting

confidence: 60%

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The MST4–MOB4 complex disrupts the MST1–MOB1 complex in the Hippo–YAP pathway and plays a pro-oncogenic role in pancreatic cancer

Chen

Zhang

Shi

et al. 2018

Journal of Biological Chemistry

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The mammalian STE20-like protein kinase 1 (MST1)-MOB kinase activator 1 (MOB1) complex has been shown to suppress the oncogenic activity of Yes-associated protein (YAP) in the mammalian Hippo pathway, which is involved in the development of multiple tumors, including pancreatic cancer (PC). However, it remains unclear whether other MST-MOB complexes are also involved in regulating Hippo-YAP signaling and have potential roles in PC. Here, we report that mammalian STE20-like kinase 4 (MST4), a distantly related ortholog of the MST1 kinase, forms a complex with MOB4 in a phosphorylation-dependent manner. We found that the overall structure of the MST4-MOB4 complex resembles that of the MST1-MOB1 complex, even though the two complexes exhibited opposite biological functions in PC. In contrast to the tumor-suppressor effect of the MST1-MOB1 complex, the MST4-MOB4 complex promoted growth and migration of PANC-1 cells. Moreover, expression levels of MST4 and MOB4 were elevated in PC and were positively correlated with each other, whereas MST1 expression was down-regulated. Because of divergent evolution of key interface residues, MST4 and MOB4 could disrupt assembly of the MST1-MOB1 complex through alternative pairing and thereby increased YAP activity. Collectively, these findings identify the MST4-MOB4 complex as a noncanonical regulator of the Hippo-YAP pathway with an oncogenic role in PC. Our findings highlight that although MST-MOB complexes display some structural conservation, they functionally diverged during their evolution.

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Section: Discussionsupporting

confidence: 60%

“…1A) (11)(12)(13)(14)(15). Furthermore, MOB3A/ B/C can associate with and negatively regulate MST1-mediated apoptosis to support tumorigenesis in glioblastoma multiforme (16), indicative of distinct roles of MST-MOB pairing. Currently, however, the physical and functional interplay between MST kinases and MOB adaptors remains only partially understood.…”

mentioning

confidence: 99%

The MST4–MOB4 complex disrupts the MST1–MOB1 complex in the Hippo–YAP pathway and plays a pro-oncogenic role in pancreatic cancer

Chen

Zhang

Shi

et al. 2018

Journal of Biological Chemistry

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“…In contrast, Class III and IV Mobs can physically associate with Hippo and Hippo-like kinases, in some cases as part of a STRIPAK complex. Thus, Class III and IV Mobs also contribute to regulation of Hippo signaling (Tang et al, 2014).…”

Section: Shared Structure and Distinguishing Features Between The Foumentioning

confidence: 99%

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

Duhart

Raftery

2020

Front. Cell Dev. Biol.

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Studies in yeast first delineated the function of Mob proteins in kinase pathways that regulate cell division and shape; in multicellular eukaryotes Mobs regulate tissue growth and morphogenesis. In animals, Mobs are adaptors in Hippo signaling, an intracellular signal-transduction pathway that restricts growth, impacting the development and homeostasis of animal organs. Central to Hippo signaling are the Nuclear Dbf2-Related (NDR) kinases, Warts and LATS1 and LATS2, in flies and mammals, respectively. A second Hippo-like signaling pathway has been uncovered in animals, which regulates cell and tissue morphogenesis. Central to this emergent pathway are the NDR kinases, Tricornered, STK38, and STK38L. In Hippo signaling, NDR kinase activation is controlled by three activating interactions with a conserved set of proteins. This review focuses on one co-activator family, the highly conserved, non-catalytic Mps1binder-related (Mob) proteins. In this context, Mobs are allosteric activators of NDR kinases and adaptors that contribute to assembly of multiprotein NDR kinase activation complexes. In multicellular eukaryotes, the Mob family has expanded relative to model unicellular yeasts; accumulating evidence points to Mob functional diversification. A striking example comes from the most sequence-divergent class of Mobs, which are components of the highly conserved Striatin Interacting Phosphatase and Kinase (STRIPAK) complex, that antagonizes Hippo signaling. Mobs stand out for their potential to modulate the output from Hippo and Hippo-like kinases, through their roles both in activating NDR kinases and in antagonizing upstream Hippo or Hippo-like kinase activity. These opposing Mob functions suggest that they coordinate the relative activities of the Tricornered/STK38/STK38L and Warts/LATS kinases, and thus have potential to assemble nodes for pathway signaling output. We survey the different facets of Mobdependent regulation of Hippo and Hippo-like signaling and highlight open questions that hinge on unresolved aspects of Mob functions.

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“…Furthermore, Tau has better inhibitory effect toward the proliferation of P53−/− tumor cells than toward P53+/+ tumor cells [10], indicating that the Tau-induced apoptosis of cancer cells is not only related to the mitochondrial apoptotic pathway but also involves other apoptotic signaling pathways. Recent studies have found that MST1 [16] and JNK [17] play important roles in the occurrence and development of colon cancer; however, whether the MST1-JNK signaling pathway is involved in the Tau-induced apoptosis of CRC cells has not been reported till date. In the present study, the CRC cell lines, SW620 and Caco-2, were used as the study subjects, in which the expression of the MST1 gene was regulated and the JNK pathway was inhibited to investigate the effect of the MST1-JNK signaling pathway in Tau-induced apoptosis of CRC cells.…”

Section: Introductionmentioning

confidence: 99%

Roles of the MST1-JNK signaling pathway in apoptosis of colorectal cancer cells induced by Taurine

Liu

Xia

Zhang

et al. 2018

Libyan Journal of Medicine

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The aim of this study was to observe the impact of the mammalian sterile 20-like kinase 1-c-Jun N-terminal kinase (MST1-JNK) signaling pathway on apoptosis in colorectal cancer (CRC) cells induced by Taurine (Tau). Caco-2 and SW620 cells transfected with p-enhanced green fluorescent protein (EGFP)-MST1 or short interfering RNA (siRNA)-MST1 were treated with Tau for 48 h. Apoptosis was detected by flow cytometry, and the levels of MST1 and JNK were detected by western blotting. Compared with the control group, 80 mM Tau could significantly induce apoptosis of CRC cells, and the apoptotic rate increased with increasing Tau concentration (P < 0.01). Meanwhile, the protein levels of MST1 and phosphorylated (p)-JNK in Caco-2 cells increased significantly (P < 0.01). The apoptotic rate of the p-EGFP-MST1 plasmid-transfected cancer cells was significantly higher than that of the control group (P < 0.05); however, the apoptotic rate of the p-EGFP-MST1+Tau group was increased further (P < 0.01). Silencing the MST1 gene could decrease the apoptotic rate of cancer cells, and Tau treatment could reverse this decrease. Blocking the JNK signaling pathway significantly reduced the Tau-induced apoptotic rate of CRC cells. Thus, the MST1-JNK pathway plays an important role in Tau-induced apoptosis of CRC cells.

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hMOB3 Modulates MST1 Apoptotic Signaling and Supports Tumor Growth in Glioblastoma Multiforme

Cited by 20 publications

References 47 publications

The MST4–MOB4 complex disrupts the MST1–MOB1 complex in the Hippo–YAP pathway and plays a pro-oncogenic role in pancreatic cancer

The MST4–MOB4 complex disrupts the MST1–MOB1 complex in the Hippo–YAP pathway and plays a pro-oncogenic role in pancreatic cancer

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

Roles of the MST1-JNK signaling pathway in apoptosis of colorectal cancer cells induced by Taurine

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