Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development

Ueda, Takeshi; Sato, Masato; Elia, Andrew; Chio, Iok In Christine; Hamada, Koichi; Fukunaga, Rikiro; Mak, Tak W.

doi:10.1073/pnas.1008136107

Cited by 189 publications

(200 citation statements)

References 51 publications

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“…Together, our combined approaches demonstrate that the MNK kinases can activate β-catenin signaling via eIF4E phosphorylation. These data add to the recent evidence supporting an important role for eIF4E phosphorylation in transformation (15,20,21,(41)(42)(43)(44)(45). Our studies also add β-catenin to the growing list of eIF4E-regulated cancerpromoting genes (15,22).…”

Section: Discussionsupporting

confidence: 57%

“…causing in vivo transformation, and also highlighted the therapeutic potential for targeting the MNK1/2 kinases, which phosphorylate eIF4E in vivo, as a way to prevent eIF4E-mediated transformation (15,20,21). Exactly how eIF4E phosphorylation contributes to cancer in these models is not entirely clear, although recent work has suggested that eIF4E phosphorylation may be particularly important for the translation of a subset of cancer-promoting mRNAs (15,22).…”

Section: Significancementioning

confidence: 99%

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Targeting of the MNK–eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function

Lim

Saw

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

129

130

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Chronic myeloid leukemia responds well to therapy targeting the oncogenic fusion protein BCR-ABL1 in chronic phase, but is resistant to treatment after it progresses to blast crisis (BC). BC is characterized by elevated β-catenin signaling in granulocyte macrophage progenitors (GMPs), which enables this population to function as leukemia stem cells (LSCs) and act as a reservoir for resistance. Because normal hematopoietic stem cells (HSCs) and LSCs depend on β-catenin signaling for self-renewal, strategies to specifically target BC will require identification of drugable factors capable of distinguishing between self-renewal in BC LSCs and normal HSCs. Here, we show that the MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis is overexpressed in BC GMPs but not normal HSCs, and that MNK kinase-dependent eIF4E phosphorylation at serine 209 activates β-catenin signaling in BC GMPs. Mechanistically, eIF4E overexpression and phosphorylation leads to increased β-catenin protein synthesis, whereas MNK-dependent eIF4E phosphorylation is required for nuclear translocation and activation of β-catenin. Accordingly, we found that a panel of small molecule MNK kinase inhibitors prevented eIF4E phosphorylation, β-catenin activation, and BC LSC function in vitro and in vivo. Our findings identify the MNK-eIF4E axis as a specific and critical regulator of BC self-renewal, and suggest that pharmacologic inhibition of the MNK kinases may be therapeutically useful in BC chronic myeloid leukemia.cancer stem cell | Wnt pathway | xenograft | biomarker

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Section: Discussionsupporting

confidence: 57%

Section: Significancementioning

confidence: 99%

Targeting of the MNK–eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function

Lim

Saw

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

129

130

View full text Add to dashboard Cite

show abstract

“…Through an integrated approach using genome-wide ChIP-sequencing and antibody microarrays, we identified MKNK1 to be a YB-1 target that is overexpressed in trastuzumabresistant cell lines. A few recent studies have suggested involvement of MNKs in tumorigenesis (Chrestensen et al, 2007;Wendel et al, 2007;Bianchini et al, 2008;Ueda et al, 2010;Grzmil et al, 2011). Our study is the first to identify a role for MNK1 in drug resistance.…”

Section: Discussionmentioning

confidence: 55%

“…Mice reconstituted with hematopoietic stem cells expressing an activated MNK1 showed accelerated lymphomagenesis, indicating that it can act as an oncogene (Wendel et al, 2007). Conversely, in a PTEN-negative lymphoma mouse model, tumorigenesis was suppressed by loss of MNK1/2 (Ueda et al, 2010). MNKs were shown to be more highly phosphorylated in HER2-positive breast cancer as compared with non-tumorigenic cells (Chrestensen et al, 2007), and their inhibition in prostate cancer cells repressed the translation of mRNAs required for cell-cycle progression (Bianchini et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

et al. 2012

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Trastuzumab (Herceptin) resistance is a major obstacle in the treatment of patients with HER2-positive breast cancers. We recently reported that the transcription factor Y-box binding protein-1 (YB-1) leads to acquisition of resistance to trastuzumab in a phosphorylationdependent manner that relies on p90 ribosomal S6 kinase (RSK). To explore how this may occur we compared YB-1 target genes between trastuzumab-sensitive cells (BT474) and those with acquired resistance (HR5 and HR6) using genome-wide chromatin immunoprecipitation sequencing (ChIP-sequencing), which identified 1391 genes uniquely bound by YB-1 in the resistant cell lines. We then examined differences in protein expression and phosphorylation between these cell lines using the Kinexus Kinex antibody microarrays. Cross-referencing these two data sets identified the mitogen-activated protein kinase-interacting kinase (MNK) family as potentially being involved in acquired resistance downstream from YB-1. MNK1 and MNK2 were subsequently shown to be overexpressed in the resistant cell lines; however, only the former was a YB-1 target based on ChIP-PCR and small interfering RNA (siRNA) studies. Importantly, loss of MNK1 expression using siRNA enhanced sensitivity to trastuzumab. Further, MNK1 overexpression was sufficient to confer resistance to trastuzumab in cells that were previously sensitive. We then developed a de novo model of acquired resistance by exposing BT474 cells to trastuzumab for 60 days (BT474LT). Similar to the HR5/HR6 cells, the BT474LT cells had elevated MNK1 levels and were dependent on it for survival. In addition, we demonstrated that RSK phosphorylated MNK1, and that this phosphorylation was required for ability of MNK1 to mediate resistance to trastuzumab. Furthermore, inhibition of RSK with the small molecule BI-D1870 repressed the MNK1-mediated trastuzumab resistance. In conclusion, this unbiased integrated approach identified MNK1 as a player in mediating trastuzumab resistance as a consequence of YB-1 activation, and demonstrated RSK inhibition as a means to overcome recalcitrance to trastuzumab.

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“…All three replicates were analyzed separately and opened in unison (results were filtered at Ͻ5% peptide FDR) to enable parallel protein grouping and quantitation. The data have been deposited to the ProteomeXchange with identifier PXD001074 (Vizcaíno et al, 2013(Vizcaíno et al, , 2014.…”

Section: Mass Spectrometry Analysismentioning

confidence: 99%

BDNF Stimulation of Protein Synthesis in Cortical Neurons Requires the MAP Kinase-Interacting Kinase MNK1

et al. 2015

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Although the MAP kinase-interacting kinases (MNKs) have been known for Ͼ15 years, their roles in the regulation of protein synthesis have remained obscure. Here, we explore the involvement of the MNKs in brain-derived neurotrophic factor (BDNF)-stimulated protein synthesis in cortical neurons from mice. Using a combination of pharmacological and genetic approaches, we show that BDNF-induced upregulation of protein synthesis requires MEK/ERK signaling and the downstream kinase, MNK1, which phosphorylates eukaryotic initiation factor (eIF) 4E. Translation initiation is mediated by the interaction of eIF4E with the m 7 GTP cap of mRNA and with eIF4G. The latter interaction is inhibited by the interactions of eIF4E with partner proteins, such as CYFIP1, which acts as a translational repressor. We find that BDNF induces the release of CYFIP1 from eIF4E, and that this depends on MNK1. Finally, using a novel combination of BONCAT and SILAC, we identify a subset of proteins whose synthesis is upregulated by BDNF signaling via MNK1 in neurons. Interestingly, this subset of MNK1-sensitive proteins is enriched for functions involved in neurotransmission and synaptic plasticity. Additionally, we find significant overlap between our subset of proteins whose synthesis is regulated by MNK1 and those encoded by known FMRP-binding mRNAs. Together, our data implicate MNK1 as a key component of BDNF-mediated translational regulation in neurons.

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Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development

Cited by 189 publications

References 51 publications

Targeting of the MNK–eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function

Targeting of the MNK–eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

BDNF Stimulation of Protein Synthesis in Cortical Neurons Requires the MAP Kinase-Interacting Kinase MNK1

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