Wnt/β-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells

Kim, Kang Ho; Seol, Ho Jun; Kim, Eun Hee; Rheey, Jinguen; Jin, Hyun Jin; Lee, Yeri; Joo, Kyeung Min; Lee, Jeongwu; Nam, Do Hyun

doi:10.1093/neuonc/nos299

Cited by 104 publications

(87 citation statements)

References 70 publications

(48 reference statements)

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“…22,23 Crosstalk between EGFR, c-Met and Wnt/b-catenin is well documented in cancer cells, thereby linking b-catenin signaling and cell migration induced by growth factors. [24][25][26][27][28][29] Thus, stimulation of epithelial cells with EGF or HGF through the phosphorylation of cell adhesion proteins diminishes cell adhesion while promoting epithelial-mesenchymal transition (EMT). Phosphorylation of Y142 b-catenin by c-Met affects b-catenin interaction with a-catenin 30 and promotes a b-catenin switch from adhesive to transcriptional functions that facilitates promigratory phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…33 Here we studied the role of b-catenin phosphorylated at Y142 (PY142) in cell invasion in GBM, a tumor in which total and dephospho S/T b-catenin (a classical Wnt transducer; hereon active b-catenin) have already received some attention. 20,34,35 We used GBM biopsies, cell lines and cell cultures established from tumoral tissue. Our findings identify a nuclear pool of PY142 b-catenin in GBM cells.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

et al. 2015

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Glioblastoma multiforme (GBM) is a fast growing brain tumor characterized by extensive infiltration into the surrounding tissue and one of the most aggressive cancers. GBM is the most common glioma (originating from glialderived cells) that either evolves from a low grade astrocytoma or appears de novo. Wnt/b-catenin and Hepatocyte Growth Factor (HGF)/c-Met signaling are hyperactive in human gliomas, where they regulate cell proliferation, migration and stem cell behavior. We previously demonstrated that b-catenin is phosphorylated at Y142 by recombinant c-Met kinase and downstream of HGF signaling in neurons. Here we studied phosphoY142 (PY142) b-catenin and dephospho S/T b-catenin (a classical Wnt transducer) in glioma biopsies, GBM cell lines and biopsyderived glioma cell cultures. We found that PY142 b-catenin mainly localizes in the nucleus and signals through transcriptional activation in GBM cells. Tissue microarray analysis confirmed strong nuclear PY142 b-catenin immunostaining in astrocytoma and GBM biopsies. By contrast, active b-catenin showed nuclear localization only in GBM samples. Western blot analysis of tumor biopsies further indicated that PY142 and active b-catenin accumulate independently, correlating with the expression of Snail/Slug (an epithelial-mesenchymal transition marker) and Cyclin-D1 (a regulator of cell cycle progression), respectively, in high grade astrocytomas and GBMs. Moreover, GBM cells stimulated with HGF showed increasing levels of PY142 b-catenin and Snail/Slug. Importantly, the expression of mutant Y142F b-catenin decreased cell detachment and invasion induced by HGF in GBM cell lines and biopsy-derived cell cultures. Our results identify PY142 b-catenin as a nuclear b-catenin signaling form that downregulates adhesion and promotes GBM cell invasion.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

et al. 2015

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“…Then accumulating β-catenin translocates to the nucleus where it activates the transcriptional factors TCF/LEF then regulate target genes referring to cellular proliferation, differentiation, survival, and apoptosis [23]. Previous data reported that Wnt2 and Wnt5a was expressed in gliomas, and knockout of Wnt2 in human U251 glioma cells inhibited cell proliferation, invasive ability, and induces apoptosis [24]. Another experiment showed that the expression of Wnt5a was positively correlated with the proliferation of glioma cells in vitro.…”

Section: Wnt Signaling Pathwaymentioning

confidence: 99%

The progression of epithelial-mesenchymal transformation in gliomas

Tang

Huang

et al. 2017

Chin Neurosurg Jl

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Epithelial-mesenchymal transformation(EMT) is a coordinated process in which polarized epithelial cells are induced to lose adhesion from the basement membrane and obtain the properties of mesenchymal cells, including invasion and metastasis. It has been proved that EMT greatly contributes to the invasion and therapeutic resistance of various solid human cancers. However, the role of EMT in brain glioma has not yet been fully clarified. So in this review, we mainly elaborate the latest progression about the related regulatory transcription factors, key signaling pathways and microRNAs (miRNAs) of EMT in gliomas.

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“…Several preclinical studies showed that MET is highly expressed in GSCs. 29,30,43 MET enhances GSCs via inducing the expression of reprogramming transcription factors and inducing differentiated cells to form multipotent stem cells. 43 Additionally, MET pathway inhibition in GSCs inhibits tumor growth and invasiveness both in vivo and in vitro.…”

Section: Cell Migration and Invasionmentioning

confidence: 99%

Targeting MET for glioma therapy

Awad¹,

Burns

Zhang

et al. 2014

FOC

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Glioblastoma multiforme is the most common and most lethal of all primary brain tumors. Even with the standard therapy, life expectancy is still poor, with an average survival of approximately 14 months following initial diagnosis. Hence, there is an urgent need for novel treatment strategies that inhibit proliferation and angiogenesis in high-grade gliomas. One such strategy consists of inhibiting receptor tyrosine kinases, including MET and/or its ligand hepatocyte growth factor (HGF). Because of their widespread involvement in human cancer, HGF and MET have emerged as promising therapeutic targets, and some inhibitory agents that target them have already entered clinical trials. In this paper, the authors highlight recent evidence implicating HGF/MET pathway deregulation in glioblastoma multiforme, discuss therapeutic approaches to inhibit HGF/MET signaling, and summarize ongoing clinical trials targeting this pathway.

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Wnt/β-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells

Abstract: These data suggest that Wnt/β-catenin signaling is a key downstream effector of MET signaling and contributes to the maintenance of GSC and GBM malignancy.

Cited by 104 publications

References 70 publications

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

The progression of epithelial-mesenchymal transformation in gliomas

Targeting MET for glioma therapy

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