Impaired Hippo signaling promotes Rho1–JNK-dependent growth

Ma, Xianjue; Chen, Yujun; Xu, Wenyan; Wu, Nan; Li, Maoquan; Wu, Shian; Li, Qiutang; Xue, Lei

doi:10.1073/pnas.1415020112

Cited by 39 publications

(37 citation statements)

References 45 publications

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“…This makes it similarly unlikely that Yki acts upstream of JNK (Ma et al, 2015) during larval WC. However, the JNK downstream transcriptional factors, Activation Protein-1 family genes (AP-1), D-Jun and D-Fos, are required for larval WC (Lesch et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Yorkie regulates epidermal wound healing in Drosophila larvae independently of cell proliferation and apoptosis

Tsai

Anderson

Burra

et al. 2017

Developmental Biology

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Yorkie (Yki), the transcriptional co-activator of the Hippo signaling pathway, has well-characterized roles in balancing apoptosis and cell division during organ growth control. Yki is also required in diverse tissue regenerative contexts. In most cases this requirement reflects its well-characterized roles in balancing apoptosis and cell division. Whether Yki has repair functions outside of the control of cell proliferation, death, and growth is not clear. Here we show that Yki and Scalloped (Sd) are required for epidermal wound closure in the Drosophila larval epidermis. Using a GFP-tagged Yki transgene we show that Yki transiently translocates to some epidermal nuclei upon wounding. Genetic analysis strongly suggests that Yki interacts with the known wound healing pathway, Jun N-terminal kinase (JNK), but not with Platelet Derived Growth Factor/Vascular-Endothelial Growth Factor receptor (Pvr). Yki likely acts downstream of or parallel to JNK signaling and does not appear to regulate either proliferation or apoptosis in the larval epidermis during wound repair. Analysis of actin structures after wounding suggests that Yki and Sd promote wound closure through actin regulation. In sum, we found that Yki regulates an epithelial tissue repair process independently of its previously documented roles in balancing proliferation and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Yorkie regulates epidermal wound healing in Drosophila larvae independently of cell proliferation and apoptosis

Tsai

Anderson

Burra

et al. 2017

Developmental Biology

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“…On one hand, proper levels of JNK activities can upregulate Yki through Ajuba (Sun and Irvine, 2013). On the other hand, Yki can activate JNK through transcriptional up-regulation of Rho1 and JNK activities are required for Yki-induced overgrowth (Ma et al, 2015). In contrast to these positive regulations, JNK can also inhibit Yki activities in certain developmental and cellular contexts.…”

Section: Discussionmentioning

confidence: 99%

Loss of histone deacetylase HDAC1 induces cell death in Drosophila epithelial cells through JNK and Hippo signaling

Zhang

Sheng

2016

Mechanisms of Development

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Inactivation of HDAC1 and its homolog HDAC2 or addition of HDAC inhibitors in mammalian systems induces apoptosis, cell cycle arrest, and developmental defects. Although these phenotypes have been extensively characterized, the precise underlying mechanisms remain unclear, particularly in in vivo settings. In this study, we show that inactivation of Rpd3, the only HDAC1 and HDAC2 ortholog in Drosophila, induced apoptosis and clone elimination in the developing eye and wing imaginal discs. Depletion of Rpd3 by RNAi cell-autonomously increased JNK activities and decreased activities of Yki, the nuclear effecter of Hippo signaling pathway. In addition, inhibition of JNK activities largely rescued Rpd3 RNAi-induced apoptosis, but did not affect its inhibition of Yki activities. Conversely, increasing the Yki activities largely rescued Rpd3 RNAi-induced apoptosis, but did not affect its induction of JNK activities. Furthermore, inactivation of Mi-2, a core component of the Rpd3-containing NuRD complex strongly induced JNK activities; while inactivation of Sin3A, a key component of the Rpd3-containing Sin3 complex, significantly inhibited Yki activities. Taken together, these results reveal that inactivation of Rpd3 independently regulates JNK and Yki activities and that both Hippo and JNK signaling pathways contribute to Rpd3 RNAi-induced apoptosis.

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“…Hippo signaling can activate JNK signaling (Ma et al, 2015(Ma et al, , 2017. We first tested if changes in Hippo signaling activity affect JNK signaling activity in the GMR> Aβ42 background.…”

Section: Jnk Activity Is Modulated By Hippo Pathway Levels In Amyloidmentioning

confidence: 99%

“…(Tare et al, 2011;Sarkar et al, 2016). It is known that Hippo can regulate JNK signaling (Ma et al, 2015(Ma et al, , 2017. To understand if the two pathways work independently or together in triggering Aβ42-mediated neurodegeneration, we tested the reporters like puc-lacZ, a reporter for JNK activity in our study (Martin-Blanco et al, 1998).…”

Section: Activation Of C-jun-amino-terminal Kinase Signalingmentioning

confidence: 99%

A Positive Feedback Loop of Hippo- and c-Jun-Amino-Terminal Kinase Signaling Pathways Regulates Amyloid-Beta-Mediated Neurodegeneration

Irwin

Tare

Singh

et al. 2020

Front. Cell Dev. Biol.

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Alzheimer's disease (AD, OMIM: 104300) is an age-related disorder that affects millions of people. One of the underlying causes of AD is generation of hydrophobic amyloid-beta 42 (Aβ42) peptides that accumulate to form amyloid plaques. These plaques induce oxidative stress and aberrant signaling, which result in the death of neurons and other pathologies linked to neurodegeneration. We have developed a Drosophila eye model of AD by targeted misexpression of human Aβ42 in the differentiating retinal neurons, where an accumulation of Aβ42 triggers a characteristic neurodegenerative phenotype. In a forward deficiency screen to look for genetic modifiers, we identified a molecularly defined deficiency, which suppresses Aβ42-mediated neurodegeneration. This deficiency uncovers hippo (hpo) gene, a member of evolutionarily conserved Hippo signaling pathway that regulates growth. Activation of Hippo signaling causes cell death, whereas downregulation of Hippo signaling triggers cell proliferation. We found that Hippo signaling is activated in Aβ42-mediated neurodegeneration. Downregulation of Hippo signaling rescues the Aβ42-mediated neurodegeneration, whereas upregulation of Hippo signaling enhances the Aβ42-mediated neurodegeneration phenotypes. It is known that c-Jun-amino-terminal kinase (JNK) signaling pathway is upregulated in AD. We found that activation of JNK signaling enhances the Aβ42-mediated neurodegeneration, whereas downregulation of JNK signaling rescues the Aβ42-mediated neurodegeneration. We tested the nature of interactions between Hippo signaling and JNK signaling in Aβ42-mediated neurodegeneration using genetic epistasis approach. Our data suggest that Hippo signaling and JNK signaling, two independent signaling pathways, act synergistically upon accumulation of Aβ42 plaques to trigger cell death. Our studies demonstrate a novel role of Hippo signaling pathway in Aβ42-mediated neurodegeneration.

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Impaired Hippo signaling promotes Rho1–JNK-dependent growth

Cited by 39 publications

References 45 publications

Yorkie regulates epidermal wound healing in Drosophila larvae independently of cell proliferation and apoptosis

Yorkie regulates epidermal wound healing in Drosophila larvae independently of cell proliferation and apoptosis

Loss of histone deacetylase HDAC1 induces cell death in Drosophila epithelial cells through JNK and Hippo signaling

A Positive Feedback Loop of Hippo- and c-Jun-Amino-Terminal Kinase Signaling Pathways Regulates Amyloid-Beta-Mediated Neurodegeneration

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