YAP/TAZ enhance mammalian embryonic neural stem cell characteristics in a Tead-dependent manner

Han, Dasol; Byun, Sung‐Hyun; Park, Soo-Jeong; Kim, Ju‐Wan; Kim, Inhee; Ha, Soobong; Kwon, Mookwang; Yoon, Keejung

doi:10.1016/j.bbrc.2015.01.077

Cited by 37 publications

(36 citation statements)

References 30 publications

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“…Through an interaction between the PPxY (PY) motifs of LATS1/2 and the WW domains of YAP and TAZ, activated LATS1/2 lead to phosphorylation of YAP and TAZ, which results in YAP/TAZ cytoplasmic retention and β-TRCP (β-transducin repeat-containing E3 ubiquitin protein ligase)-dependent proteasomal degradation ( 9 , 10 ). When Hippo signaling is inactive or “OFF”, YAP and TAZ are localized to the nucleus, where they serve as transcriptional co-activators for TEA domain-containing sequence-specific transcription factors (TEADs) ( 17 – 21 ) as well as other transcription factors ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft-Tissue Sarcomas

Deel

Crose

et al. 2015

Front. Oncol.

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The Hippo signaling pathway is an evolutionarily conserved developmental network vital for the regulation of organ size, tissue homeostasis, repair and regeneration, and cell fate. The Hippo pathway has also been shown to have tumor suppressor properties. Hippo transduction involves a series of kinases and scaffolding proteins that are intricately connected to proteins in developmental cascades and in the tissue microenvironment. This network governs the downstream Hippo transcriptional co-activators, YAP and TAZ, which bind to and activate the output of TEADs, as well as other transcription factors responsible for cellular proliferation, self-renewal, differentiation, and survival. Surprisingly, there are few oncogenic mutations within the core components of the Hippo pathway. Instead, dysregulated Hippo signaling is a versatile accomplice to commonly mutated cancer pathways. For example, YAP and TAZ can be activated by oncogenic signaling from other pathways, or serve as co-activators for classical oncogenes. Emerging evidence suggests that Hippo signaling couples cell density and cytoskeletal structural changes to morphogenic signals and conveys a mesenchymal phenotype. While much of Hippo biology has been described in epithelial cell systems, it is clear that dysregulated Hippo signaling also contributes to malignancies of mesenchymal origin. This review will summarize the known molecular alterations within the Hippo pathway in sarcomas and highlight how several pharmacologic compounds have shown activity in modulating Hippo components, providing proof-of-principle that Hippo signaling may be harnessed for therapeutic application in sarcomas.

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Section: Introductionmentioning

confidence: 99%

A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft-Tissue Sarcomas

Deel

Crose

et al. 2015

Front. Oncol.

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“…Comparatively little is known about Taz functions in the developing brain. Overexpression experiments expressing Yap1 and Taz in NSCs implied that Tead2 is the mediator in their control of neural progenitor proliferation and neurogenesis 20 . Tead1 −/− and Tead2 −/− mice show severe growth retardation and morphological abnormalities including failure in dorsal neural tube closure as well as notochord and somite defects 21,22 .…”

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confidence: 99%

Tead transcription factors differentially regulate cortical development

Mukhtar

Breda

Grison

et al. 2020

Sci Rep

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Dagmar iber 3,4 , christian Beisel 5 , erik van nimwegen 2 & Verdon taylor 1* Neural stem cells (NSCs) generate neurons of the cerebral cortex with distinct morphologies and functions. How specific neuron production, differentiation and migration are orchestrated is unclear. Hippo signaling regulates gene expression through Tead transcription factors (TFs). We show that Hippo transcriptional coactivators Yap1/Taz and the Teads have distinct functions during cortical development. Yap1/Taz promote NSC maintenance and Satb2 + neuron production at the expense of Tbr1 + neuron generation. However, Teads have moderate effects on NSC maintenance and do not affect Satb2 + neuron differentiation. Conversely, whereas Tead2 blocks Tbr1 + neuron formation, Tead1 and Tead3 promote this early fate. In addition, we found that Hippo effectors regulate neuronal migration to the cortical plate (CP) in a reciprocal fashion, that ApoE, Dab2 and Cyr61 are Tead targets, and these contribute to neuronal fate determination and migration. Our results indicate that multifaceted Hippo signaling is pivotal in different aspects of cortical development. NSCs of the developing cerebral cortex form the ventricular zone (VZ) lining the lumen of the neural tube 1-5. NSCs in the dorsal anterior forebrain are the major source of the projection neurons of the cerebral cortex 4,5. The mechanisms controlling the patterning and cell fate specification of these stem cells during early brain development are not clearly understood. Although various signaling pathways including Notch, Wnt, Shh, FGFs, TGF-β, Retinoic acid, Reelin and Hippo are known to regulate NSC proliferation and to control fate decisions, neurogenesis, and gliogenesis; the crosstalk between the different signaling pathways and the integration of these signals on target genes governing complex cell fate choices is unclear 1-3. Hippo signaling is evolutionarily conserved and a regulator of organ size control and tissue homeostasis 6-9. The pathway is regulated by numerous stimuli including G-protein coupled receptor signaling, mechanical stress, cellular energy status, cell-cell contact and cell-extra-cellular matrix interactions 6-8. Hippo signaling employs a cascade of phosphorylation steps mediated by the kinases Mst1/2 and Lats1/2 8-10. Lats1/2 phosphorylate the transcriptional coregulators Yap1 and Taz to promote cytoplasmic retention and subsequent degradation 6-8. When Hippo signaling is inactive, Yap1/Taz translocate to the nucleus and form multiple complexes with different DNA binding partners including TEADs, SMADs, and Runx TFs (Fig. S1a) 8-10. The Teads are major regulators of Hippo target genes in many systems including cancer 8,11,12. Fat4 and Dchs are receptor and ligand, respectively, of the Hippo pathway in embryonic NSCs. Knockdown of Fat4 results in increased proliferation in the developing nervous system and reduction of neuronal differentiation 13,14. Mutations in FAT4 and DCHS cause Van Maldergem syndrome in humans, an autosomal-recessive disorder characterized by in...

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“…1A,B). To test the functions of TRBP in embryonic neural progenitor cells in vitro, we began with neurospheres (Singec et al, 2006) isolated after transducing E14.5 neural progenitors with a TRBP-expressing retroviral vector MSIG (Han et al, 2015). Expression of TRBP gave rise to an increase in the number and size of neurospheres compared with control virus (Fig.…”

Section: Resultsmentioning

confidence: 99%

TRBP maintains mammalian embryonic neural stem cell properties by enhancing the Notch signaling pathway as a novel transcriptional coactivator

et al. 2017

Self Cite

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Transactivation response element RNA-binding protein (TRBP) is known to play important roles in human immunodeficiency virus (HIV) replication and microRNA biogenesis. However, recent studies implicate TRBP in a variety of biological processes as a mediator for cross-talk between signal transduction pathways. Here, we provide the first evidence that TRBP is required for efficient neurosphere formation, and expression of neural stem cell markers and Notch target genes in primary neural progenitor cells in vitro. Consistent with this, introduction of TRBP into the mouse embryonic brain in utero increased the fraction of cells expressing Sox2 in the ventricular zone (VZ). We also show TRBP physically interacts with the Notch transcriptional coactivation complex through C promoter binding factor 1 (CBF1) and strengthens the association between the Notch intracellular domain (NICD) and CBF1, resulting in increased NICD recruitment to the promoter region of a Notch target gene. Our data indicate that TRBP is a novel transcriptional coactivator of the Notch signaling pathway playing an important role in neural stem cell regulation during mammalian brain development.

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YAP/TAZ enhance mammalian embryonic neural stem cell characteristics in a Tead-dependent manner

Cited by 37 publications

References 30 publications

A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft-Tissue Sarcomas

A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft-Tissue Sarcomas

Tead transcription factors differentially regulate cortical development

TRBP maintains mammalian embryonic neural stem cell properties by enhancing the Notch signaling pathway as a novel transcriptional coactivator

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