VGLL4 and MENIN function as TEAD1 corepressors to block pancreatic β cell proliferation

Li, Feng; Liu, Ruya; Negi, Vinny; Yang, Ping; Lee, Jeongkyung; Jagannathan, Rajaganapathi; Moulik, Mousumi; Yechoor, Vijay

doi:10.1016/j.celrep.2022.111904

Cited by 13 publications

(6 citation statements)

References 40 publications

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“…A potential drawback of inhibiting TEAD is that TEAD has different coactivators and corepressors that modulate its activity. One of the corepressors is VGLL4 (Vestigial-like family member 4), which can repress TEAD-mediated transcription [ 31 – 33 ]. When TEAD is inhibited, it not only affects the activation of certain TEAD target genes but also leads to the repression of TEAD-VGLL4 complexes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the YAP-MMB interaction and targeting NEK2 as potential therapeutic strategies for YAP-driven cancers

Jessen,

Gertzmann,

Liss

et al. 2024

Oncogene

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YAP activation in cancer is linked to poor outcomes, making it an attractive therapeutic target. Previous research focused on blocking the interaction of YAP with TEAD transcription factors. Here, we took a different approach by disrupting YAP’s binding to the transcription factor B-MYB using MY-COMP, a fragment of B-MYB containing the YAP binding domain fused to a nuclear localization signal. MY-COMP induced cell cycle defects, nuclear abnormalities, and polyploidization. In an AKT and YAP-driven liver cancer model, MY-COMP significantly reduced liver tumorigenesis, highlighting the importance of the YAP-B-MYB interaction in tumor development. MY-COMP also perturbed the cell cycle progression of YAP-dependent uveal melanoma cells but not of YAP-independent cutaneous melanoma cell lines. It counteracted YAP-dependent expression of MMB-regulated cell cycle genes, explaining the observed effects. We also identified NIMA-related kinase (NEK2) as a downstream target of YAP and B-MYB, promoting YAP-driven transformation by facilitating centrosome clustering and inhibiting multipolar mitosis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the YAP-MMB interaction and targeting NEK2 as potential therapeutic strategies for YAP-driven cancers

Jessen,

Gertzmann,

Liss

et al. 2024

Oncogene

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“…Vestigial-like protein 4 (Vgll4) is a transcriptional cofactor that can bind directly to TEAD proteins, via its tandem Tondu domain (TDU), thereby competing for the Yap-TEAD interaction and thus mechanistically acting as an inhibitor of Yap activity ( Koontz et al, 2013 ; Jiao et al, 2014 ; Zhang et al, 2014 ; Li et al, 2023 ). In Xenopus and zebrafish the transcripts of the different vgll4 paralogs show a dynamic developmental expression pattern in different tissues ( Faucheux et al, 2010 ; Barrionuevo et al, 2014 ; Xue et al, 2018 ) and in zebrafish the mRNA of two ( Xue et al, 2018 ) ( vgll4a ; vgll4b ) of the three paralogs ( vgll4a , vgll4b and vgll4l ) have been detected at the 1 cell stage ( Xue et al, 2018 ), suggesting a possible early function.…”

Section: Introductionmentioning

confidence: 99%

Maternal vgll4a regulates zebrafish epiboly through Yap1 activity

Camacho-Macorra,

Tabanera,

Sánchez-Bustamante

et al. 2024

Front. Cell Dev. Biol.

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Gastrulation in zebrafish embryos commences with the morphogenetic rearrangement of blastodermal cells, which undergo a coordinated spreading from the animal pole to wrap around the egg at the vegetal pole. This rearrangement, known as epiboly, relies on the orchestrated activity of maternal transcripts present in the egg, compensating for the gradual activation of the zygotic genome. Epiboly involves the mechano-transducer activity of yap1 but what are the regulators of yap1 activity and whether these are maternally or zygotically derived remain elusive. Our study reveals the crucial role of maternal vgll4a, a proposed Yap1 competitor, during zebrafish epiboly. In embryos lacking maternal/zygotic vgll4a (MZvgll4a), the progression of epiboly and blastopore closure is delayed. This delay is associated with the ruffled appearance of the sliding epithelial cells, decreased expression of yap1-downstream targets and transient impairment of the actomyosin ring at the syncytial layer. Our study also shows that, rather than competing with yap1, vgll4a modulates the levels of the E-cadherin/β-catenin adhesion complex at the blastomeres’ plasma membrane and hence their actin cortex distribution. Taking these results together, we propose that maternal vgll4a acts at epiboly initiation upstream of yap1 and the E-cadherin/β-catenin adhesion complex, contributing to a proper balance between tissue tension/cohesion and contractility, thereby promoting a timely epiboly progression.

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“…However, in comparison to YAP and TAZ, little is known about their functional regulation. Among the VGLL proteins, VGLL4 and its Drosophila homolog Tgi have been demonstrated as the transcriptional repressors by competing with YAP/TAZ binding to TEAD through two TONDU (TDU) domains (Koontz et al, 2013; Cai et al, 2022; Zhang et al, 2014; Li et al, 2023). In contrast, the precise function of VGLL1-3 in both normal and tumor cells and how they influence Hippo/YAP signaling and affect TEAD transcriptional output remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300

Guo,

Hu,

Cotton

et al. 2024

Preprint

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Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEAD. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 and TEAD1-NCOA2, recently identified in spindle cell rhabdomyosarcoma. We demonstrate that, in contrast to VGLL2 and TEAD1, the fusion proteins are strong activators of TEAD-dependent transcription, and their function does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase p300 to control TEAD-mediated transcriptional and epigenetic landscapes. We showed that small molecule p300 inhibition can suppress fusion proteins-induced oncogenic transformation bothin vitroandin vivo. Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying VGLL, TEAD, or NCOA translocations.

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VGLL4 and MENIN function as TEAD1 corepressors to block pancreatic β cell proliferation

Cited by 13 publications

References 40 publications

Inhibition of the YAP-MMB interaction and targeting NEK2 as potential therapeutic strategies for YAP-driven cancers

Inhibition of the YAP-MMB interaction and targeting NEK2 as potential therapeutic strategies for YAP-driven cancers

Maternal vgll4a regulates zebrafish epiboly through Yap1 activity

VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300

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