Loss of the cell polarity gene could cooperate with oncogenic Ras to drive tumor growth and invasion, which critically depends on the c-Jun N-terminal Kinase (JNK) signaling pathway in Drosophila. By performing a genetic screen, we have identified Src42A, the ortholog of mammalian Src, as a key modulator of both Ras^V12/lgl^−/− triggered tumor invasion and loss of cell polarity gene-induced cell migration. Our genetic study further demonstrated that the Bendless (Ben)/dUev1a ubiquitin E2 complex is an essential regulator of Src42A-induced, JNK-mediated cell migration. Furthermore, we showed that ectopic Ben/dUev1a expression induced invasive cell migration along with increased MMP1 production in wing disc epithelia. Moreover, Ben/dUev1a could cooperate with Ras^V12 to promote tumor overgrowth and invasion. In addition, we found that the Ben/dUev1a complex is required for ectopic Src42A-triggered cell death and endogenous Src42A-dependent thorax closure. Our data not only provide a mechanistic insight into the role of Src in development and disease but also propose a potential oncogenic function for Ubc13 and Uev1a, the mammalian homologs of Ben and dUev1a.

Signalling networks that control the life or death of a cell are of central interest in modern biology. While the defined roles of the c-Jun N-terminal kinase (JNK) pathway in regulating cell death have been well-established, additional factors that modulate JNK-mediated cell death have yet to be fully elucidated. To identify novel regulators of JNK-dependent cell death, we performed a dominant-modifier screen inDrosophilaand found that the Toll pathway participates in JNK-mediated cell death. Loss of Toll signalling suppresses ectopically and physiologically activated JNK signalling-induced cell death. Our epistasis analysis suggests that the Toll pathway acts as a downstream modulator for JNK-dependent cell death. In addition, gain of JNK signalling results in Toll pathway activation, revealed by stimulated transcription ofDrosomycin(Drs) and increased cytoplasm-to-nucleus translocation of Dorsal. Furthermore, the Spätzle (Spz) family ligands for the Toll receptor are transcriptionally upregulated by activated JNK signalling in a non-cell-autonomous manner, providing a molecular mechanism for JNK-induced Toll pathway activation. Finally, gain of Toll signalling exacerbates JNK-mediated cell death and promotes cell death independent of caspases. Thus, we have identified another important function for the evolutionarily conserved Toll pathway, in addition to its well-studied roles in embryonic dorso-ventral patterning and innate immunity.

Significance: Cancer is the leading cause of death worldwide, although studies revealed that dysregulation of the Hippo pathway contributes to tumorigenesis, whereas its roles in tumor invasion and cell migration remain paradoxical and largely elusive. Using Drosophila as a model, we herein find cross-talk between the Hippo and JNK pathways in regulating cell migration and invasion. Mechanistically, we identify bantam -Rox8 modules as essential components downstream of Yorkie in mediating JNK-dependent cell invasion. Our finding is particularly important as it offers a wake-up call for therapeutic interventions of Hippo-related cancers, because simply increasing Hippo signal activity may paradoxically accelerate cell invasion and metastasis.

The amyloid precursor protein (APP) is a broadly expressed transmembrane protein that has a significant role in the pathogenesis of Alzheimer’s disease (AD). APP can be cleaved at multiple sites to generate a series of fragments including the amyloid β (Aβ) peptides and APP intracellular domain (AICD). Although Aβ peptides have been proposed to be the main cause of AD pathogenesis, the role of AICD has been underappreciated. Here we report that APP induces AICD-dependent cell death in Drosophila neuronal and non-neuronal tissues. Our genetic screen identified the transcription factor forkhead box O (FoxO) as a crucial downstream mediator of APP-induced cell death and locomotion defect. In mammalian cells, AICD physically interacts with FoxO in the cytoplasm, translocates with FoxO into the nucleus upon oxidative stress, and promotes FoxO-induced transcription of pro-apoptotic gene Bim. These data demonstrate that APP modulates FoxO-mediated cell death through AICD, which acts as a transcriptional co-activator of FoxO.

Abnormal aggregation of misfolded pathological proteins in neurons is a prominent feature of neurodegenerative disorders including Parkinson’s disease (PD). Perturbations of proteostasis at the endoplasmic reticulum (ER) triggers ER stress, activating the unfolded protein response (UPR). Chronic ER stress is thought to underlie the death of neurons during the neurodegenerative progression, but the precise mechanism by which the UPR pathways regulate neuronal cell fate remains incompletely understood. Here we report a critical neurodegenerative role for inositol-requiring enzyme 1 (IRE1), the evolutionarily conserved ER stress sensor, in a Drosophila model of PD. We found that IRE1 was hyperactivated upon accumulation of α-synuclein in the fly photoreceptor neurons. Ectopic overexpression of IRE1 was sufficient to trigger autophagy-dependent neuron death in an XBP1-independent, JNK-dependent manner. Furthermore, IRE1 was able to promote dopaminergic neuron loss, progressive locomotor impairment, and shorter lifespan, whereas blocking IRE1 or ATG7 expression remarkably ameliorated the progression of α-synuclein-caused Parkinson’s disease. These results provide in vivo evidence demonstrating that the IRE1 pathway drives PD progression through coupling ER stress to autophagy-dependent neuron death.