Proteomic screening identifies a YAP-driven signaling network linked to tumor cell proliferation in human schwannomas

Boin, Alizée; Couvelard, Anne; Couderc, Christophe; Brito, Isabel Martínez; Filipescu, Dan; Kalamaridès, Michel; Bédossa, Pierre; Koning, Leanne de; Danelsky, Carine; Dubois, Thierry; Hupé, Philippe; Louvard, Daniel; Lallemand, Dominique

doi:10.1093/neuonc/nou020

Cited by 28 publications

(27 citation statements)

References 48 publications

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“…Axl expression has been shown to be important in a wide range of other tumors, [49][50][51][52] including merlin-deficient tumors such as schwannomas and mesotheliomas, 49,53,54 but there are no data available for its potential role in meningiomas. The frequent expression of Axl found in meningiomas in our study suggests that further study of its potential role in meningioma growth is warranted, and if a functional role is confirmed then it offers further therapeutic options.…”

Section: Discussionmentioning

confidence: 99%

Activation of multiple growth factor signalling pathways is frequent in meningiomas

et al. 2015

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A minority of meningiomas are difficult to treat with surgery or radiotherapy, and chemotherapeutic alternatives are limited. This study aims to better understand pathways that are active in meningiomas, in order to direct future treatment strategies. We investigated the expression and activation of multiple growth factor receptors, their ligands and downstream signalling pathways in 30 meningiomas using immunohistochemistry. Expression was correlated with chromosome 22q loss. Membrane expression of VEGF receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR)β was seen in 83% of tumors, Axl in 70%, EGFR in 50% and insulin-like growth factor receptor in 47%. Expression was similar in low- and high-grade tumors, but membrane EGFR expression was not seen in tumors showing chromosome 22q loss (P < 0.05). Expression of ligands (IGF, NRG, VEGF, Gas 6), and signalling proteins (Mek, Erk, Jnk, Akt) and pS6RP, was widespread. Western blot confirmed widespread Axl expression and supported selective expression of EGFR in NF2-intact meningiomas. The majority of meningiomas express and show activation of multiple growth factor receptors and their signalling pathways, irrespective of tumor grade. In addition to previously reported receptors, Axl offers a new therapeutic target. The findings also suggest that anti-EGFR based therapies may be less effective in meningiomas with 22q loss.

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Section: Discussionmentioning

confidence: 99%

Activation of multiple growth factor signalling pathways is frequent in meningiomas

et al. 2015

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“…24 YAP is considered as the main effector of the Hippo signalling pathway in various organisms and tissues. 25 Knockdown of lncRNA GHET1 suppresses the cell proliferation and invasion by down-regulating YAP1 expression in the non-small cell lung cancer. 26 YAP-1 functions as an oncogenic and a putative prognostic biomarker of recurrence in patients with PTC.…”

Section: Discussionmentioning

confidence: 99%

“…29 Dephosphorylated YAP allows its entry into nucleus where it activates the transcription of proproliferative and anti-apoptotic targets. 25 YAP can be phosphorylated and made inactive by alive LATS1. 30 A study has showed that downregulated lncRNA taurine-up-regulated gene 1 (TUG1) occurs with decreased YAP levels.…”

Section: Discussionmentioning

confidence: 99%

Long non‐coding RNA TNRC6C‐AS1 promotes methylation of STK4 to inhibit thyroid carcinoma cell apoptosis and autophagy via Hippo signalling pathway

Peng

Tan

et al. 2019

J Cellular Molecular Medi

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The role of long non‐coding RNAs (lncRNAs) in thyroid carcinoma (TC), the most frequent endocrine malignancy, has been extensively examined. This study investigated effect of interaction among lncRNA TNRC6C‐AS1, serine/threonine‐protein kinase 4 (STK4) and Hippo signalling pathway on TC. Initially, lncRNA TNRC6C‐AS1 expression in TC tissues was detected. To explore roles of lncRNA TNRC6C‐AS1, STK4 and Hippo signalling pathway in TC progression, their expressions were altered. Interaction between lncRNA TNRC6C‐AS1 and STK4, STK4 promoter methylation, or Hippo signalling pathway was verified. After that, a series of experiments were employed to evaluate in vitro ability of apoptosis, proliferation and autophagy of TC cells and in vivo tumorigenicity, and tumour growth of TC cells. lncRNA TNRC6C‐AS1 was highly expressed while STK4 was poorly expressed in TC tissues. LncRNA TNRC6C‐AS1 promoted the STK4 methylation and down‐regulated STK4 expression, which further activated the Hippo signalling pathway. STK4 silencing was observed to promote the proliferation ability of TC cells, inhibit the apoptosis and autophagy abilities, as well as enhance the tumorigenicity and tumour growth. Moreover, the in vitro proliferation ability as well as the in vivo tumorigenicity and tumour growth of TC cells were inhibited after the blockade of Hippo signalling pathway, while the apoptosis and autophagy abilities were promoted. The results demonstrate that the lncRNA TNRC6C‐AS1 increases STK4 promoter methylation to down‐regulate STK4 expression, thereby promoting the development of TC through activation of Hippo signalling pathway. It highlights that lncRNA TNRC6C‐AS1 may be a novel therapeutic target for the treatment of TC.

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“…Finally, Merlin is a major regulator of the Hippo signaling pathway by inhibiting the nuclear accumulation of the cotranscription factor Yap and Taz in various organisms (11,12). Although these mechanisms initially appeared distinct, cross talks were identified between several of them (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of Merlin by Aurora A kinase appears necessary for mitotic progression

Mandati

Maestro

Dingli

et al. 2019

Journal of Biological Chemistry

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Although Merlin function as a tumor suppressor and regulator of mitogenic signaling networks such as the Ras/rac, Akt or Hippo pathways is well documented,in mammals as well as in insects, its role during cell cycle progression remains unclear. In this study, using a combination of approaches, including FACS analysis, time-lapse imaging, immunofluorescence microscopy and coimmunoprecipitation, we show that Ser-518 of Merlin is a substrate of the Aurora A kinase during mitosis and that its phosphorylation facilitates the phosphorylation of a newly discovered site, Thr-581. We found that the expression in Hela cells of a Merlin variant that is phosphorylation-defective on both sites leads to a defect in centrosomes and mitotic spindles positioning during metaphase and delays the transition from metaphase to anaphase. We also show that the dual mitotic phosphorylation not only reduces Merlin binding to microtubules but also timely modulates Ezrin interaction with the cytoskeleton. Finally, we identify several point mutants of Merlin associated with Neurofibromatosis type 2 that display an aberant phosphorylation profile along with defective α-tubulin binding properties. Altogether, our findings of an Aurora A-mediated interaction of Merlin with α-tubulin and Ezrin suggest a potential role for Merlin in cell cycle progression.

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Proteomic screening identifies a YAP-driven signaling network linked to tumor cell proliferation in human schwannomas

Cited by 28 publications

References 48 publications

Activation of multiple growth factor signalling pathways is frequent in meningiomas

Activation of multiple growth factor signalling pathways is frequent in meningiomas

Long non‐coding RNA TNRC6C‐AS1 promotes methylation of STK4 to inhibit thyroid carcinoma cell apoptosis and autophagy via Hippo signalling pathway

Phosphorylation of Merlin by Aurora A kinase appears necessary for mitotic progression

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