Salt Inducible Kinases as Novel Notch Interactors in the DevelopingDrosophilaRetina

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 understanding tumorigenesis and cancer progression. Salt inducible kinases (Siks) are evolutionarily conserved genes involved in diverse biological processes, including salt sensing, metabolism, muscle and skeletal development. Recent findings implicate SIKs in tumor suppression or progression. However, their role in development remains largely unknown. Using a sensitized tumor model in the Drosophila eye, we show that perturbations of Sik function exacerbates tumor-like tissue overgrowth and metastasis. Furthermore, we show that both Drosophila Sik genes, Sik2 and Sik3 , are required for proper eye development. We propose that an important target of Siks may be the Notch pathway, as we demonstrate epistasis between Siks and Notch pathway members and identify putative phosphorylation motifs on Notch, Delta and Fringe. Finally, we investigate Sik expression in the developing retina and show that Sik2 is expressed in all photoreceptors in close proximity 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 in tissue specification, growth, and that their dysregulation may contribute to tumor formation.