View Program - 63rd Annual Drosophila Research Conference

Homeodomain-interacting protein kinases (Hipks) are conserved kinases that regulate cell proliferation, apoptosis and tissue development. Hipks have been shown to regulate the activity of many key conserved signaling pathways, including Wnt, Notch, Hippo and Jak/Stat. Overexpression of Hipk in Drosophila causes tumorigenic phenotypes. We primarily examine tissue overgrowth and distortion in larval imaginal discs. We found that co-expression of a constitutively active form of Salt-inducible kinase 2 (Sik2) or Sik3 with Hipk caused significant tissue overgrowth and tissue distortion, indicating that both Sik2 and Sik3 can synergize with Hipk to promote tumour growth. Larvae expressing these neoplastic growths also display an extended larval phase, characteristic of Drosophila tumor models. SIKs are serine/threonine protein kinases belonging to the adenosine monophosphate (AMP)-activated protein kinase (AMPK) family. While mammals have SIK 1-3, Drosophila only has Sik2 (mammalian ortholog of SIK1 and SIK2) and Sik3. Furthermore, depletion of Sik 2 or Sik3 can suppress overgrowth phenotypes due to Hipk overexpression. Examination of total protein levels from fly tissues showed that Hipk proteins were reduced when Siks were depleted through RNAi or by using mutant alleles. These results suggest that Siks may regulate Hipk protein stability and/or activity. Furthermore, Siks are known to regulate several signal transduction cascades by phosphorylating key components of these pathways. Preliminary data from the lab has shown that Sik2 can be co-immunoprecipitated with Hipk. In summary, our research demonstrates a novel function of Siks in synergizing with Hipk to promote tumour growth potentially. We are investigating the mechanism underlying these interactions and hypothesize that Siks phosphorylate Hipks to modulate their stability and or activity. Gaining further insight into tumorigenic synergies has potential implications of finding drug targets in the future that could block tumour growth via inhibition of Siks.

Salt-inducible kinases synergise with Homeodomain-interacting protein kinases to promote significant tumour growth