PP6 Disruption Synergizes with Oncogenic Ras to Promote JNK-Dependent Tumor Growth and Invasion

Ma, Xianjue; Lu, Juanjuan; Dong, Yang; Li, Daming; Malagon, Juan Nicolas; Xu, Tian

doi:10.1016/j.celrep.2017.05.092

Cited by 32 publications

(33 citation statements)

References 39 publications

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“…We did not observe a difference between wild type and PpV mutant clones (Figure 6B). Consistent with recent reports that depleting PpV by RNAi in eye and wing imaginal discs (Chi et al 2018; Ma et al 2017), our data indicate that PpV is not required for proliferation of cells in larval imaginal discs.…”

Section: Resultssupporting

confidence: 93%

“…In Drosophila , Protein phosphatase V ( PpV ) encodes the homolog of the catalytic subunit of human PP6 (Bastians and Ponstingl 1996; Mann et al 1993). PpV has been implicated by various types of experiments in the AMPK and JNK pathways, showing functions in lipid homeostasis, apoptosis, as well as tumorigenesis (Chi et al 2018; Ma et al 2017; Yin et al 2014). However, the physiological and developmental functions of PpV have been little known due to lack of a genetically defined mutant.…”

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confidence: 99%

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Multiple Functions of the Essential GenePpVinDrosophilaEarly Development

Liu

Sung

Großhans

2019

G3 Genes|Genomes|Genetics

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Protein phosphatase V (PpV) encodes the Drosophila homolog of the evolutionarily conserved Protein Phosphatase 6 (PP6). The physiological and developmental functions of PpV/PP6 have not been well characterized due to lack of a genetically defined mutant. Here, we identified a PpV non-sense mutation and describe multiple mutant phenotypes in oogenesis and early embryogenesis. Specifically, we found that the defects in chromosome segregation during nuclear cycles are related to AuroraA function, which is consistent with the interaction of PP6 and AuroraA in mammalian cells. Surprisingly, we also identified a PpV function specifically in blastoderm cell cycle but not in cell proliferation in the follicle epithelium or larval wing imaginal discs. Embryos from PpV germline clones frequently undergo an extra nuclear division cycle. By epistasis analysis, we found that PpV functions in parallel with tribbles, but independently of auroraA for the remodeling of the nuclear cycles. Taken together, this study reports novel developmental functions of PpV and provides a framework for further genetic analysis under physiological conditions.

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Section: Resultssupporting

confidence: 93%

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confidence: 99%

Multiple Functions of the Essential GenePpVinDrosophilaEarly Development

Liu

Sung

Großhans

2019

G3 Genes|Genomes|Genetics

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“…Moreover, overexpression of the E2 ubiquitin ligase, Ben/dUev1a, which activates JNK signalling, also cooperates with Ras V12 to promote invasive tumour growth [ 94 ] ( Table 1 ). More recently, loss of function mutations in the PP6 phosphatase have been shown to act upstream of the Tak1 protein kinase, a JNKKK, to induce invasive tumorigenesis in Ras V12 -expressing eye-antennal epithelial cells [ 97 ]. Furthermore, in the adult Drosophila hindgut epithelium, JNK activation through the Egr (TNF) pathway, in response to bacterial infection, also cooperates with Ras V12 to promote invasive overgrowth [ 92 , 98 ] ( Table 1 ).…”

Section: Cooperation Interactions Between Oncogenic or Tumour-suppmentioning

confidence: 99%

Modelling Cooperative Tumorigenesis inDrosophila

Richardson

Portela

2018

BioMed Research International

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The development of human metastatic cancer is a multistep process, involving the acquisition of several genetic mutations, tumour heterogeneity, and interactions with the surrounding microenvironment. Due to the complexity of cancer development in mammals, simpler model organisms, such as the vinegar fly, Drosophila melanogaster, are being utilized to provide novel insights into the molecular mechanisms involved. In this review, we highlight recent advances in modelling tumorigenesis using the Drosophila model, focusing on the cooperation of oncogenes or tumour suppressors, and the interaction of mutant cells with the surrounding tissue in epithelial tumour initiation and progression.

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“…4a) and invasion into the ventral nerve cord (VNC) (Fig. 4e) 6,38 , a previously established in vivo model to study the mechanism of tumor invasion 19,32,39 . Consistent with previous data indicating that the JNK signaling plays a crucial role in Ras v12 /lgl −/− -induced tumor invasion 19,20 , expression of Puc completely blocked tumor cell invasion to VNC (Fig.…”

Section: Resultsmentioning

confidence: 99%

MKK3 modulates JNK-dependent cell migration and invasion

et al. 2019

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The c-Jun N-terminal kinase (JNK) pathway plays essential roles in regulating a variety of physiological processes including cell migration and invasion. To identify critical factors that regulate JNK-dependent cell migration, we carried out a genetic screen in Drosophila based on the loss-of-cell polarity-triggered cell migration in the wing epithelia, and identified MKK3 licorne (lic) as an essential regulator of JNK-mediated cell migration and invasion. We found that loss of lic suppressed ptc > scrib-IR or ptc > Egr triggered cell migration in the wing epithelia, and Rasv12/lgl−/− induced tumor invasion in the eye discs. In addition, ectopic expression of Lic is sufficient to induce JNK-mediated but p38-independent cell migration, and cooperate with oncogenic Ras to promote tumor invasion. Consistently, Lic is able to activate JNK signaling by phosphorylating JNK, which up-regulates the matrix metalloproteinase MMP1 and integrin, characteristics of epithelial–mesenchymal transition (EMT). Moreover, lic is required for physiological JNK-mediate cell migration in thorax development. Finally, expression of human MKK3 in Drosophila is able to initiate JNK-mediated cell migration, cooperates with oncogenic Ras to trigger tumor invasion, and rescue loss-of-lic induced thorax closure defect. As previous studies suggest that MKK3 specifically phosphorylates and activates p38MAPK, our data provide the first in vivo evidence that MKK3 regulates JNK-dependent cell migration and invasion, a process evolutionarily conserved from flies to human.

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PP6 Disruption Synergizes with Oncogenic Ras to Promote JNK-Dependent Tumor Growth and Invasion

Cited by 32 publications

References 39 publications

Multiple Functions of the Essential GenePpVinDrosophilaEarly Development

Multiple Functions of the Essential GenePpVinDrosophilaEarly Development

Modelling Cooperative Tumorigenesis inDrosophila

MKK3 modulates JNK-dependent cell migration and invasion

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