Salt inducible kinases as novel Notch interactors in the developing Drosophila retina

Abstract

Developmental processes require strict regulation of proliferation, differentiation and patterning for the generation of final organ size. Aberrations in these fundamental events are critically important in tumorigenesis and cancer progression. Salt inducible kinases (Siks) are evolutionarily conserved genes involved in diverse biological processes, including salt sensing, metabolism, muscle, cartilage and bone formation, but their role in development remains largely unknown. Recent findings implicate Siks in mitotic control, and in both tumor suppression and progression. Using a tumor model in the Drosophila eye, we show that perturbation of Sik function exacerbates tumor-like tissue overgrowth and metastasis. Furthermore, we show that both Drosophila Sik genes, Sik2 and Sik3, function in eye development processes. We propose that an important target of Siks may be the Notch signaling pathway, as we demonstrate genetic interaction between Siks and Notch pathway members. Finally, we investigate Sik expression in the developing retina and show that Sik2 is expressed in all photoreceptors, basal to cell junctions, while Sik3 appears to be expressed specifically in R3/R4 cells in the developing eye. Combined, our data suggest that Sik genes are important for eye tissue specification and growth, and that their dysregulation may contribute to tumor formation.

The AMPK-like protein kinases Sik2 and Sik3 interact with Hipk and induce synergistic tumorigenesis in a Drosophila cancer model

“…In addition, it has also been shown that induced activation of oncogenic Ras and Src in the Drosophila eye epithelia resulted in small benign tumors, however when co-expressed with Sik2-CA resulted in tumor overgrowth ( Hirabayashi and Cagan, 2015 ). A study by Şahin et al (2020) showed complex genetic interactions including potent synergy of Sik2 and Sik3 with a Notch-based tumor model. These results demonstrate that like the results of this study, different oncogenic mutations can synergise to produce tumor overgrowths.…”

“…In addition, research in Drosophila has found that Sik2 and Sik3 are upstream regulators of the Hippo signalling pathway, a conserved pathway that is vital for controlling organ size, and Sik2 can increase Yki target gene expression and promote tumorigenesis ( Wehr et al, 2013 ; Hirabayashi and Cagan, 2015 ). Siks were also found to mediate tumorigenesis via Notch signaling in a combinatorial cancer model involving overexpression of the Notch ligand Delta and loss of chromatin modifiers ( Şahin et al, 2020 ).…”

Numerous Serine/Threonine Kinases Affect Blood Cell Homeostasis in Drosophila melanogaster

“…A loss of crystal cells was also seen upon the ubiquitous but not the hemocyte-specific induction of Gskt and Sik2 S1032A . The former shares similarities with GSK3 kinase, a core component of the Wnt signaling pathway, whereas the latter regulates energy homeostasis as well as Notch signal transduction [57,69,70]. Hence, both may have a more general role in proliferation and development.…”