Ras-activated Dsor1 promotes Wnt signaling in Drosophila development

Abstract

Wnt/Wingless (Wg) and Ras-MAPK signaling both play fundamental roles in growth and cell fate determination, and when dysregulated, can lead to tumorigenesis. Several conflicting modes of interaction between Ras-MAPK and Wnt signaling have been identified in specific cellular contexts, causing synergistic or antagonistic effects on target genes. We find novel evidence that the Drosophila homolog of the dual specificity kinases MEK1/2 (also known as MAP2K1/2), Downstream of Raf1 (Dsor1), is required for Wnt signaling. Knockdown of Dsor1 results in loss of Wg target gene expression, as well as reductions in stabilized Armadillo (Arm; Drosophila β-catenin). We identify a close physical interaction between Dsor1 and Arm, and find that catalytically inactive Dsor1 causes a reduction in active Arm. These results suggest that Dsor1 normally counteracts the Axin-mediated destruction of Arm. We find that Ras-Dsor1 activity is independent of upstream activation by EGFR, and instead it appears to be activated by the insulin-like growth factor receptor to promote Wg signaling. Taken together, our results suggest that there is a new crosstalk pathway between insulin and Wg signaling that is mediated by Dsor1.

Actomyosin contractility modulates Wnt signaling through adherens junction stability

“…As our results indicate myosin phosphatase likely affects Wg signaling through inactivation of NMII (Fig S3N), in subsequent experiments knockdown of myosin phosphatase will be used as a proxy for specifically stimulating NMII. Since increased NMII activity led to reduced stabilized Arm and a loss of Wg target gene expression, we next asked if NMII could affect destruction complex proteins in Drosophila salivary gland cells, as their large cells are ideal for studying protein localization in vivo, and glands have been characterized with respect to Wg signaling [25].…”

“…After Wg binds to its receptors in the proximal cells of the salivary gland, Dsh, Axin and other the components of the destruction complex are recruited to Fz (Fig 2B), causing inactivation of the complex [26]. flw-RNAi had no effect on the cell surface distribution of Dsh-GFP or FLAG-Axin (Fig 2B), compared to other proteins previously identified to affect recruitment to the membrane [25], indicating that Wg’s regulation of the destruction complex still occurs in cells with elevated NMII activity. These results suggest that increased NMII activity affects Wg signaling downstream of the receptors.…”

TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer

“…A possible explanation may be the subcellular distributions of b-CATENIN and TNKS. In Drosophila, active RAS signaling counteracts AXIN-mediated degradation of Armadillo (the Drosophila b-CATENIN) by recruiting the destruction complex to the cell membrane (48). In accordance, dual inhibition of TNKS and MEK has shown to be efficacious in KRAS-mutant colorectal cancers (12,17).…”

Rotation of sex combs in Drosophila melanogaster requires precise and coordinated spatio-temporal dynamics from forces generated by epithelial cells

“…For example, joint formation is not included in our simulations yet previous studies have pointed out that it affects the basal part of SC [ 13 ] and constitutes the male-specific movement of sensillum campaniforme [ 15 ]. Effects of joint formation on SC rotation can be studied using photo-activated lines that can disrupt development precisely [ 36 , 37 ].…”