同源结构域相互作用蛋白激酶 (Hipks) 调节细胞增殖、凋亡和组织发育。 Hipk 在果蝇中的过度表达会导致幼虫成虫盘中的致瘤表型。我们发现盐诱导激酶 Sik2 或 Sik3 的消耗可以抑制 Hipk 诱导的过度生长。此外，Sik2或Sik3的组成型活性形式与Hipk的共表达引起显着的组织增生和组织扭曲，表明Sik2和Sik3都可以与Hipk协同促进肿瘤表型，伴随着dMyc、犰狳/β-连环蛋白的升高和约克夏目标基因得到扩展。表达这些增生性生长的幼虫也表现出延长的幼虫期，这是其他果蝇肿瘤模型的特征。对果蝇组织总蛋白水平的检查表明，当 Siks 通过 RNAi 耗尽时，Hipk 蛋白会减少，这表明 Siks 可能调节 Hipk 蛋白的稳定性和/或活性。相反，组成型活性 Siks 与 Hipk 的表达会导致 Hipk 蛋白水平增加。此外，Hipk 可以通过免疫共沉淀与 Sik2 和 Sik3 相互作用。两种蛋白的共表达导致 Hipk 蛋白的迁移率发生变化，表明它发生了翻译后修饰。总之，我们的研究证明了 Siks 与 Hipk 协同促进肿瘤生长的新功能。版权所有 © 2023 Yu、Ramkumar、Wong、Tettweiler 和 Verheyen。

Homeodomain-interacting protein kinases (Hipks) regulate cell proliferation, apoptosis, and tissue development. Overexpression of Hipk in Drosophila causes tumorigenic phenotypes in larval imaginal discs. We find that depletion of Salt-inducible kinases Sik2 or Sik3 can suppress Hipk-induced overgrowth. Furthermore, co-expression of constitutively active forms of Sik2 or Sik3 with Hipk caused significant tissue hyperplasia and tissue distortion, indicating that both Sik2 and Sik3 can synergize with Hipk to promote tumorous phenotypes, accompanied by elevated dMyc, Armadillo/β-catenin, and the Yorkie target gene expanded. Larvae expressing these hyperplastic growths also display an extended larval phase, characteristic of other Drosophila tumour models. Examination of total protein levels from fly tissues showed that Hipk proteins were reduced when Siks were depleted through RNAi, suggesting that Siks may regulate Hipk protein stability and/or activity. Conversely, expression of constitutively active Siks with Hipk leads to increased Hipk protein levels. Furthermore, Hipk can interact with Sik2 and Sik3 by co-immunoprecipitation. Co-expression of both proteins leads to a mobility shift of Hipk protein, suggesting it is post-translationally modified. In summary, our research demonstrates a novel function of Siks in synergizing with Hipk to promote tumour growth.Copyright © 2023 Yu, Ramkumar, Wong, Tettweiler and Verheyen.