Hippo signaling promotes JNK-dependent cell migration

Ma, Xianjue; Wang, Hongxiang; Ji, Jiansong; Xu, Wenyan; Sun, Yihao; Li, Wenzhe; Zhang, Xiaoping; Chen, Juxiang; Xue, Lei

doi:10.1073/pnas.1621359114

Cited by 67 publications

(67 citation statements)

References 56 publications

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“…Expression of puc can prevent ptc>dCskRNAi cells from spreading at the A/P boundary (Vidal et al, 2006). JNK activity is also needed for ykiRNAi cells to invade across the wing disc A/P boundary, and co-expression of bsk DN and ykiRNAi blocks this invasion (Ma et al, 2017). Consistent with the role JNK in BCE regulation, blocking JNK signaling by bsk DN expression can prevent ykiRNAi cells from being extruded to the basal side of the wing epithelia (Fig.…”

Section: Jnk Signaling Mediates Hpo-activation-induced Cell Extrusionsupporting

confidence: 52%

“…2B). It is known that activated Hpo plays a role in cell-migration (Ma et al, 2017). yki-depleted cells migrated across the A/P boundary and extruded basally, and this cell migration was suppressed by ban.…”

Section: Activated Hpo Pathway Induces Cell Extrusion In the Drosophimentioning

confidence: 99%

“…In addition to roles in apoptosis and cell proliferation, the Hpo pathway has been recently implicated in cell extrusion and invasion, which may help to explain the poor survival of yki mutant clones. Expression of ykiRNAi along the anterior/posterior (A/P) boundary of Drosophila wing discs induces cell migration across the A/P boundary and basal cell extrusion (BCE) (Ma et al, 2017). However, except for apoptosis induced BCE, whether cell extrusion causes the abnormal Hpo-Yki signaling-induced poor recovery rate is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Hippo signaling promotes Ets21c-dependent apical cell extrusion in theDrosophilawing disc

Wang

Zhang

et al. 2020

Preprint

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STATEMENT Activation of Hippo signaling induces cell extrusion in the Drosophila wing epithelia, in which bantam mediates basal cell extrusion and Ets21c mediates apical cell extrusion. ABSTRACT Cell extrusion is a crucial regulator of epithelial tissue development and homeostasis. Epithelial cells undergoing apoptosis, bearing pathological mutations, and possessing developmental defects are actively extruded toward elimination. However, the molecular mechanisms of Drosophila epithelial cell extrusion are not fully understood.Here, we report that activation of the conserved Hippo (Hpo) signaling pathway induces both apical and basal cell extrusion in the Drosophila wing disc epithelia. We show that canonical Yorki targets Diap1, and that dMyc and Cyclin E are not required for either apical or basal cell extrusion induced by activation of this pathway. Another target gene, bantam, is only involved in basal cell extrusion, suggesting novel Hpo-regulated apical cell extrusion mechanisms. Using RNA-Seq analysis, we found that JNK signaling is activated in the extruding cells. We provide genetic evidence that JNK signaling activation is both sufficient and necessary for Hpo-regulated cell extrusion. Furthermore, we demonstrate that the ETS-domain transcription factor Ets21c, an ortholog of proto-oncogenes FLI1 and ERG, acts downstream of JNK signaling to mediate apical cell extrusion. Our findings reveal a novel molecular link between Hpo signaling and cell extrusion.

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Section: Jnk Signaling Mediates Hpo-activation-induced Cell Extrusionsupporting

confidence: 52%

Section: Activated Hpo Pathway Induces Cell Extrusion In the Drosophimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hippo signaling promotes Ets21c-dependent apical cell extrusion in theDrosophilawing disc

Wang

Zhang

et al. 2020

Preprint

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“…It has recently been hypothesized that phosphorylated JNK acts as an inducer of Drp1 activation [27] and that Yap has the ability to regulate JNK phosphorylation [25]. To determine whether Yap influences Drp1-mediated fission via JNK, we first assessed changes of JNK.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, recent studies have indicated that the Hippo-pathway facilitates mitochondrial function via Bcl-xL [24], demonstrating a possible relationship between Yap and cytoplasmic mitochondria. Furthermore, accumulating evidence has described the regulatory action of Yap on JNK [25, 26]. Thus, together with the confirmed role of JNK in initiating mitochondrial fission [27], these findings raise the possibility that Yap may govern mitochondrial fission via JNK.…”

Section: Introductionmentioning

confidence: 89%

YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

Zhao

et al. 2017

Cell Physiol Biochem

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Background/Aims: The Hippo-Yap pathway is associated with tumor development and progression. However, little evidence is available concerning its role in cancer cell apoptosis and migration via mitochondrial homeostasis. Here, we identify mitochondrial fission as a regulator of the Hippo–Yap pathway in human rectal cancer tumorigenesis and metastasis. Methods: In this study, we performed loss-of function assays concerning Yap in RCC via shRNA. Cellular viability and apoptosis were measured via MTT, the TUNEL assay and trypan blue staining. Mitochondrial function was assessed via JC1 staining, the mPTP opening assay, mitochondrial respiratory function analysis, electron microscopy and immunofluorescence analysis of HtrA2/Omi. Mitophagy and mitochondrial fission were assessed via western blots and immunofluorescence. Cell migration was evaluated via the Transwell assay, wound-healing assay and immunofluorescence analysis of F-actin. The interaction between JNK and Yap was detected via co-immunoprecipitation and Yap recombinant mutagenic plasmid transfection. Western blots were used to analyze signaling pathways in conjunction with JNK inhibitors or HtrA2/Omi siRNA. Results: Yap is upregulated in human rectal cancer cells, where its expression correlates positively with cell survival and migration. Functional studies established that silencing of Yap drove JNK phosphorylation, which induced Drp1 activation and translocation to the surface of mitochondria, initiating mitochondrial fission. Excessive mitochondrial fission mediated HtrA2/Omi leakage from the mitochondria into the cytoplasm, where HtrA2/Omi triggered cellular apoptosis via the mitochondrial apoptosis pathway. Moreover, released HtrA2/Omi also phosphorylated cofilin and inhibited cofilin-mediated F-actin polymerization. F-actin collapse perturbed lamellipodia formation and therefore impaired cellular migration and invasion. Conclusion: Collectively, our results demonstrate that Hippo-Yap can serve as a tumor promoter in human rectal cancer and acts by restricting JNK/Drp1/mitochondrial fission/ HtrA2/Omi, with potential implications for new approaches to human rectal cancer therapy.

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Gp93 inhibits unfolded protein response‐mediated c‐Jun N‐terminal kinase activation and cell invasion

Xu,

Wu,

et al. 2024

Journal Cellular Physiology

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In eukaryotes, Hsp90B1 serves as a vital chaperonin, facilitating the accurate folding of proteins. Interestingly, Hsp90B1 exhibits contrasting roles in the development of various types of cancers, although the underlying reasons for this duality remain enigmatic. Through the utilization of the Drosophila model, this study unveils the functional significance of Gp93, the Drosophila ortholog of Hsp90B1, which hitherto had limited reported developmental functions. Employing the Drosophila cell invasion model, we elucidated the pivotal role of Gp93 in regulating cell invasion and modulating c‐Jun N‐terminal kinase (JNK) activation. Furthermore, our investigation highlights the involvement of the unfolded protein response‐associated IRE1/XBP1 pathway in governing Gp93 depletion‐induced, JNK‐dependent cell invasion. Collectively, these findings not only uncover a novel molecular function of Gp93 in Drosophila, but also underscore a significant consideration pertaining to the testing of Hsp90B1 inhibitors in cancer therapy.

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Hippo signaling promotes JNK-dependent cell migration

Cited by 67 publications

References 56 publications

Hippo signaling promotes Ets21c-dependent apical cell extrusion in theDrosophilawing disc

Hippo signaling promotes Ets21c-dependent apical cell extrusion in theDrosophilawing disc

YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

Gp93 inhibits unfolded protein response‐mediated c‐Jun N‐terminal kinase activation and cell invasion

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