Hippo signaling suppresses tumor cell metastasis via a Yki-Src42A positive feedback loop

Ding, Yan; Wang, Guiping; Zhan, Meixiao; Sun, Xuxu; Deng, Yanran; Zhao, Yunhe; Liu, Bin; Liu, Qingxin; Wu, Shian; Zhou, Zizhang

doi:10.1038/s41419-021-04423-y

Cited by 11 publications

(6 citation statements)

References 71 publications

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“…In Drosophila, the enhancement of cell migration induced by the inhibition of Scrib was shown to be mediated by Yki. 66 Furthermore, it was shown that cancer-associated phenotypes may be induced by the interaction between Scrib and Yap, which inhibits the activity of YAP. 67 In addition, apical and basal domains are physically separated by cell junction complexes.…”

Section: Key Components Of the Hippo Pathwaymentioning

confidence: 99%

The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

219

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As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in the regulation of numerous biological processes. Thus, substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway, as well as its physiological functions, such as cell proliferation and differentiation, organ growth, embryogenesis, and tissue regeneration/wound healing. However, dysregulation of the Hippo pathway can cause a variety of diseases, including cancer, eye diseases, cardiac diseases, pulmonary diseases, renal diseases, hepatic diseases, and immune dysfunction. Therefore, therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases. Here, we review the key components and upstream signals of the Hippo pathway, as well as the critical physiological functions controlled by the Hippo pathway. Additionally, diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.

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Section: Key Components Of the Hippo Pathwaymentioning

confidence: 99%

The Hippo signalling pathway and its implications in human health and diseases

Lan

et al. 2022

Sig Transduct Target Ther

219

View full text Add to dashboard Cite

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“…Loss of Scrib cell polarity regulator strongly promotes metastasis behavior of cancer cells [27]. To examine the contribution of Drp1 mitochondrial fission protein and involvement of JNK signaling to prevent metastatic behavior in Scrib abrogated cells, we tagged Ptc-Gal4 driver line with GFP.…”

Section: Resultsmentioning

confidence: 99%

“…Scrib is mislocalized to the cytoplasm of cancer cells upon loss of function mutation in Scrib complex proteins [41–43]. The loss of function mutation of Scrib leads to development of neoplastic tumor [27,44]. Earlier reports from our laboratory showed larval wing tissue specific knockdown of Scrib developed neoplastic tumors with increased larval size and die as giant pupae during early stages of pupal development without differentiation [14].…”

Section: Discussionmentioning

confidence: 99%

Drp1-JNKknockdown mitigates Scribble loss induced cell proliferation, metastasis and lethality phenotypes inDrosophila

Singh,

Srikrishna

2024

Preprint

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Mitochondrial dynamics are emerging as master regulators for targeting several types of cancers, including breast cancer, cervical cancer, and hepatocellular carcinoma, for therapeutic intervention. Mitochondrial morphology, size, position and activity within cells is regulated by dynamic fission and fusion events. Dynamin-related protein 1 (Drp1) promotes mitochondrial fission and maintains mitochondrial homeostasis. Loss ofScribis implicated in several human cancers wherein mitochondrial dysfunction leads to excessive cell proliferation and metastasis. However, the exact molecular mechanisms behind theScribloss induced dysregulation of mitochondrial dynamics in cancer progression remains obscure. Although the role of mitochondrial dynamics are being investigated in several types of cancers, but the role ofDrp1- mediated fission event in regulating the maintenance of polarity of cells upon loss ofScribfunction is elusive. In this study, for the first time, we blocked the function ofDrp1activity inScribknockdown induced metastasis cancer model by two ways, firstly, through genetic ablation ofDrp1,and secondly by using mdivi-1, aDrp1specific inhibitor. Genetic depletion ofDrp1expression (Drp1RNAi) inScribknockdown cells inhibits MetalloproteinaseMMP1, reduces ROS production, restores apico-basal (A/B) cell polarity and enhances ATP production. Further to confirm role of Drp1 in regulation of cell polarity, we employed mdivi, a Drp1 specific inhibitor which has dose dependent effect in cell polarity regulation. This study also reveals thatJNKinhibition (JNKRNAi) inScribabrogated cells mitigates theDrp1expression and controls cell proliferation leading to restoration of mitochondrial morphology and epithelial cellpolarity. Our results highlightDrp1as a key regulator in maintaining the apico-basal polarity of cells which gets affected upon loss ofScribbutDrp1-JNKdownregulation effectively mitigatesScribRNAiassociated cell proliferation, metastasis and pupal lethality phenotypes.

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“…Immunostaining of wing discs was carried out according to our previous protocols 61 . Briefly, third-instar larvae were dissected in PBS and fixed in 4% PFA at room temperature for 20 min, then permeabilized with PBT (PBS supplemented with 0.1% Triton X-100) for three times.…”

Section: Methodsmentioning

confidence: 99%

The AAA-ATPase Ter94 regulates wing size in Drosophila by suppressing the Hippo pathway

Li,

Ding,

Deng

et al. 2024

Commun Biol

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Insect wing development is a fascinating and intricate process that involves the regulation of wing size through cell proliferation and apoptosis. In this study, we find that Ter94, an AAA-ATPase, is essential for proper wing size dependently on its ATPase activity. Loss of Ter94 enables the suppression of Hippo target genes. When Ter94 is depleted, it results in reduced wing size and increased apoptosis, which can be rescued by inhibiting the Hippo pathway. Biochemical experiments reveal that Ter94 reciprocally binds to Mer, a critical upstream component of the Hippo pathway, and disrupts its interaction with Ex and Kib. This disruption prevents the formation of the Ex-Mer-Kib complex, ultimately leading to the inactivation of the Hippo pathway and promoting proper wing development. Finally, we show that hVCP, the human homolog of Ter94, is able to substitute for Ter94 in modulating Drosophila wing size, underscoring their functional conservation. In conclusion, Ter94 plays a positive role in regulating wing size by interfering with the Ex-Mer-Kib complex, which results in the suppression of the Hippo pathway.

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Hippo signaling suppresses tumor cell metastasis via a Yki-Src42A positive feedback loop

Cited by 11 publications

References 71 publications

The Hippo signalling pathway and its implications in human health and diseases

The Hippo signalling pathway and its implications in human health and diseases

Drp1-JNKknockdown mitigates Scribble loss induced cell proliferation, metastasis and lethality phenotypes inDrosophila

The AAA-ATPase Ter94 regulates wing size in Drosophila by suppressing the Hippo pathway

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