Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner

Lee, Yoonmi; Kim, Nam Hee; Cho, Eunae Sandra; Yang, Ji Hye; Hoon, Yong; Kang, Hee Eun; Yun, Jung Won; Cho, Sue Bean; Lee, Seon-Hyeong; Paclíková, Petra; Radaszkiewicz, Tomasz; Bryja, Vı́tězslav; Kang, Chi Gu; Yuk, Young Soo; Young, So; Kim, Soo-Youl; Kim, Hyun Sil; Yook, Jong In

doi:10.1038/s41467-018-04757-w

Cited by 61 publications

(55 citation statements)

References 68 publications

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“…YAP can be phosphorylated by VP, and phosphorylated YAP binds to proteins and remains in the cytoplasm [28,29]. Therefore, the destruction of YAP/TAZ nuclear transport by VP can inhibit the EMT process to a certain extent [30], a nding that was also con rmed in this study.…”

Section: Discussionsupporting

confidence: 81%

LGR5 promotes invasion and migration by regulating YAP activity in hypopharyngeal squamous cell carcinoma cells

Zhu

Wen

et al. 2020

Preprint

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Background High leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) expression caused by an inflammatory microenvironment was reported to promote tumor proliferation and the epithelial–mesenchymal transition (EMT) in various malignant tumors, but those effects have not been studied in hypopharyngeal squamous cell carcinoma (HSCC) and the molecular mechanism remains unclear. Additionally, YAP/TAZ, an upstream or downstream factor of multiple signaling pathways, can promote tumor proliferation, invasion, and angiogenesis. Our study was aimed to determine whether YAP/TAZ is involved in the regulation of LGR5 expression in the inflammatory microenvironment.Methods We stimulated FaDu cells, a hypopharyngeal squamous cell carcinoma cell line, with inflammatory medium. The expression levels of EMT-related proteins, LGR5, and p-YAP were detected by reverse transcription–polymerase chain reaction, western blotting, and immunofluorescence.Results The results showed that LGR5 expression and the EMT process were significantly enhanced. The expression of EMT-related proteins was up-regulated, while that of p-YAP was decreased. After inhibiting the high LGR5 expression with short interfering RNA, the expression of EMT-related proteins was also down-regulated, while that of p-YAP was significantly increased. The use of verteporfin (VP), an inhibitor of YAP activity that promotes YAP phosphorylation, did not affect LGR5 expression.Conclusions Our findings suggest that the inflammatory microenvironment leads to high LGR5 expression, up-regulating the expression of EMT-related proteins by inhibiting the YAP phosphorylation.

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Section: Discussionsupporting

confidence: 81%

LGR5 promotes invasion and migration by regulating YAP activity in hypopharyngeal squamous cell carcinoma cells

Zhu

Wen

et al. 2020

Preprint

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“…Some evidence suggests potential cooperativity between these proteins in the context of tumorigenesis. Dvl physically interacts with phosphorylated YAP, promoting YAP nuclear export, and suppressing its transcriptional activity, while treatment with Wnt1 or Wnt3a induces YAP dephosphorylation, reducing its binding to Dvl and thus promoting its nuclear translocation (Lee et al, 2018). Given that Wnt5a also induces YAP dephosphorylation (Park et al, 2015), Wnt5a might also activate YAP by abrogating its binding to Dvl, thus promoting YAP nuclear translocation.…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

Wnt5a Signaling in Gastric Cancer

Astudillo

2020

Front. Cell Dev. Biol.

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Gastric cancer remains an important health challenge, accounting for a significant number of cancer-related deaths worldwide. Therefore, a deeper understanding of the molecular mechanisms involved in gastric cancer establishment and progression is highly desirable. The Wnt pathway plays a fundamental role in development, homeostasis, and disease, and abnormal Wnt signaling is commonly observed in several cancer types. Wnt5a, a ligand that activates the non-canonical branch of the Wnt pathway, can play a role as a tumor suppressor or by promoting cancer cell invasion and migration, although the molecular mechanisms explaining these roles have not been fully elucidated. Wnt5a is increased in gastric cancer samples; however, most gastric cancer cell lines seem to exhibit little expression of this ligand, thus raising the question about the source of this ligand in vivo. This review summarizes available research about Wnt5a expression and signaling in gastric cancer. In gastric cancer, Wnt5a promotes invasion and migration by modulating integrin adhesion turnover. Disheveled, a scaffolding protein with crucial roles in Wnt signaling, mediates the adhesion-related effects of Wnt5a in gastric cancer cells, and several studies provide growing support for a model whereby Disheveled-interacting proteins mediates Wnt5a signaling to modulate cytoskeleton dynamics. However, Wnt5a might induce other effects in gastric cancer cells, such as cell survival and induction of gene expression. On the other hand, the available evidence suggests that Wnt5a might be expressed by cells residing in the tumor microenvironment, where feedback mechanisms sustaining Wnt5a secretion and signaling might be established. This review analyzes the possible functions of Wnt5a in this pathological context and discusses potential links to mechanosensing and YAP/TAZ signaling.

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“…In Drosophila Yki nuclear export has been shown to also depend on other factors. For example, Yki can interact directly with the Wnt‐related protein Dishevelled (Dvl), which has a NES (Lee et al, ).…”

Section: Overview Of the Hippo‐yap Signaling Pathwaymentioning

confidence: 99%

Hippo‐Yap/Taz signaling: Complex network interactions and impact in epithelial cell behavior

Soldt

Cardoso

2019

WIREs Developmental Biology

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The Hippo pathway has emerged as a crucial integrator of signals in biological events from development to adulthood and in diseases. Although extensively studied in Drosophila and in cell cultures, major gaps of knowledge still remain on how this pathway functions in mammalian systems. The pathway consists of a growing number of components, including core kinases and adaptor proteins, which control the subcellular localization of the transcriptional co‐activators Yap and Taz through phosphorylation of serines at key sites. When localized to the nucleus, Yap/Taz interact with TEAD transcription factors to induce transcriptional programs of proliferation, stemness, and growth. In the cytoplasm, Yap/Taz interact with multiple pathways to regulate a variety of cellular functions or are targeted for degradation. The Hippo pathway receives cues from diverse intracellular and extracellular inputs, including growth factor and integrin signaling, polarity complexes, and cell–cell junctions. This review highlights the mechanisms of regulation of Yap/Taz nucleocytoplasmic shuttling and their implications for epithelial cell behavior using the lung as an intriguing example of this paradigm. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Signaling Pathways > Cell Fate Signaling Establishment of Spatial and Temporal Patterns > Cytoplasmic Localization

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Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner

Cited by 61 publications

References 68 publications

LGR5 promotes invasion and migration by regulating YAP activity in hypopharyngeal squamous cell carcinoma cells

LGR5 promotes invasion and migration by regulating YAP activity in hypopharyngeal squamous cell carcinoma cells

Wnt5a Signaling in Gastric Cancer

Hippo‐Yap/Taz signaling: Complex network interactions and impact in epithelial cell behavior

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