Biology subjects

Verheyen, E. M.

Publications and source records attributed to Verheyen, E. M..

3 recordsLinked to original sources

bioRxiv2017

Actomyosin contractility modulates Wnt signaling through adherens junction stability

Mechanical forces can influence the canonical Wnt signaling pathway in processes like mesoderm differentiation and tissue stiffness during tumorigenesis, but a molecular mechanism involving both in a developing epithelium and its homeostasis is lacking. We identified that increased non-muscle myosin II activation and cellular contraction inhibited Wnt target gene transcription in developing Drosophila. Genetic interactions studies identified this effect was due to myosin-induced accumulation of cortical F-actin resulting in clustering and accumulation of E-cadherin to the adherens junctions. E-cadherin titrates any available {beta}-catenin, the Wnt pathway transcriptional co-activator, to the adherens junctions in order to maintain cell-cell adhesion under contraction. We show that decreased levels of cytoplasmic {beta}-catenin result in insufficient nuclear translocation for full Wnt target gene transcription. Our work elucidates a mechanism in which the dynamic activation of actomyosin contractility refines patterning of Wnt transcription during development and maintenance of epithelial tissue in organisms.

cell biology↗

bioRxiv2017

Homeodomain interacting protein kinase promotes tumorigenesis and metastatic cell behavior

Aberrations in signaling pathways that regulate tissue growth often lead to tumorigenesis. Homeodomain interacting protein kinase (Hipk) family members are reported to have distinct and contradictory effects on cell proliferation and tissue growth. From these studies it is clear that much remains to be learned about the roles of Hipk family protein kinases in proliferation and cell behaviour. Previous work has shown that Drosophila Hipk is a potent growth regulator, thus we predicted that it could have a role in tumorigenesis. In our study of Hipk-induced phenotypes, we observed the formation of tumor-like structures in multiple cell types in larvae and adults. Furthermore, elevated Hipk in epithelial cells induces cell spreading, invasion and epithelial-to-mesenchymal transition in the imaginal disc. Further evidence comes from cell culture studies in which we expressed Drosophila Hipk in human breast cancer cells and show that it enhances proliferation and migration. Past studies have shown that Hipk can promote the action of conserved pathways implicated in cancer and EMT, such as Wnt/Wingless, Hippo, Notch and JNK. We show that Hipk-phenotypes are not likely due to activation of a single target, but rather through a cumulative effect on numerous target pathways. Most Drosophila tumor models involve mutations in multiple genes, such as the well-known RasV12 model, in which EMT and invasiveness occur after the additional loss of the tumor suppressor gene scribble. Our study reveals that elevated levels of Hipk on their own can promote both hyperproliferation and invasive cell behaviour, suggesting that Hipks could be potent oncogenes and drivers of EMT.\n\nSummary statementThe protein kinase Hipk can promote proliferation and invasive behaviors, as well as synergize with known cancer pathways, in a novel Drosophila model for tumorigenesis.

cancer biology↗

bioRxiv2017

The Protein Phosphatase 4 complex promotes the Notch 1pathway and wg transcription

The Wnt/Wingless (Wg) pathway controls cell fate specification, tissue differentiation and organ development across organisms. Using an in vivo RNAi screen to identify novel kinase and phosphatase regulators of the Wg pathway, we identified subunits of the serine threonine phosphatase Protein phosphatase 4 (PP4). Knockdown of the catalytic and the regulatory subunits of PP4 cause reductions in the Wg pathway targets Senseless and Distal-less. We find that PP4 regulates the Wg pathway by controlling Notch-driven wg transcription. Genetic interaction experiments identified that PP4 likely promotes Notch signaling within the nucleus of the Notch-receiving cell. Although the PP4 complex is implicated in various cellular processes, its role in the regulation of Wg and Notch pathways was previously uncharacterized. Our study identifies a novel role of PP4 in regulating Notch pathway, resulting in aberrations in Notch-mediated transcriptional regulation of the Wingless ligand. Furthermore, we show that PP4 regulates proliferation independent of its interaction with Notch.\n\nSummary statementThe protein phosphatase 4 complex promotes Notch signaling and target gene expression during Drosophila wing development.

developmental biology↗