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Polarity protein Canoe mediates overproliferation via modulation of JNK, Ras-MAPK and Hippo signalling.

ABSTRACT: OBJECTIVES:Over the past decade an intriguing connection between cell polarity and tumorigenesis has emerged. Multiple core components of the junction complexes that help to form and maintain cell polarity display both pro- and anti-tumorigenic functions in a context-dependent manner, with the underlying mechanisms poorly understood. MATERIALS AND METHODS:With transgenic fly lines that overexpress or knock down specific signalling components, we perform genetic analysis to investigate the precise role of the polarity protein Canoe (Cno) in tumorigenesis and the downstream pathways. RESULTS:We show that overexpression of cno simultaneously activates JNK and Ras-MEK-ERK signalling, resulting in mixed phenotypes of both overproliferation and cell death in the Drosophila wing disc. Moderate alleviation of JNK activation eliminates the effect of Cno on cell death, leading to organ overgrowth and cell migration that mimic the formation and invasion of tumours. In addition, we find that the Hippo pathway acts downstream of JNK and Ras signalling to mediate the effect of Cno on cell proliferation. CONCLUSIONS:Our work reveals an oncogenic role of Cno and creates a new type of Drosophila tumour model for cancer research.

SUBMITTER: Ma Z

PROVIDER: S-EPMC6430484 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Polarity protein Canoe mediates overproliferation via modulation of JNK, Ras-MAPK and Hippo signalling.

Ma Zhiwei Z Li Ping P Hu Xingjie X Song Haiyun H

Cell proliferation 20181017 1

<h4>Objectives</h4>Over the past decade an intriguing connection between cell polarity and tumorigenesis has emerged. Multiple core components of the junction complexes that help to form and maintain cell polarity display both pro- and anti-tumorigenic functions in a context-dependent manner, with the underlying mechanisms poorly understood.<h4>Materials and methods</h4>With transgenic fly lines that overexpress or knock down specific signalling components, we perform genetic analysis to investi ...[more]

PMID: 30328653

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Project description:c-Jun N-terminal kinase (JNK) is a multi-functional protein involved in a diverse array of context-dependent processes, including apoptosis, cell cycle regulation, adhesion, and differentiation. It is integral to several signalling cascades, notably downstream of non-canonical Wnt and mitogen activated protein kinase (MAPK) signalling pathways. As such, it is a key regulator of cellular behaviour and patterning during embryonic development across the animal kingdom. The cephalochordate amphioxus is an invertebrate chordate model system straddling the invertebrate to vertebrate transition and is thus ideally suited for comparative studies of morphogenesis. However, next to nothing is known about JNK signalling or cellular processes in this lineage. Pharmacological inhibition of JNK signalling using SP600125 during embryonic development arrests gastrula invagination and causes convergence extension-like defects in axial elongation, particularly of the notochord. Pharynx formation and anterior oral mesoderm derivatives like the preoral pit are also affected. This is accompanied by tissue-specific transcriptional changes, including reduced expression of six3/6 and wnt2 in the notochord, and ectopic wnt11 in neurulating embryos treated at late gastrula stages. Cellular delamination results in accumulation of cells in the gut cavity and a dorsal fin-like protrusion, followed by secondary Caspase-3-mediated apoptosis of polarity-deficient cells, a phenotype only partly rescued by co-culture with the pan-Caspase inhibitor Z-VAD-fmk. Ectopic activation of extracellular signal regulated kinase (ERK) signalling in the neighbours of extruded notochord and neural cells, possibly due to altered adhesive and tensile properties, as well as defects in cellular migration, may explain some phenotypes caused by JNK inhibition. Overall, this study supports conserved functions of JNK signalling in mediating the complex balance between cell survival, apoptosis, differentiation, and cell fate specification during cephalochordate morphogenesis.

Dataset Information

Polarity protein Canoe mediates overproliferation via modulation of JNK, Ras-MAPK and Hippo signalling.

Publications

Polarity protein Canoe mediates overproliferation via modulation of JNK, Ras-MAPK and Hippo signalling.

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