Verheyen Esther M, Swarup Sharan, Lee Wendy
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
Fly (Austin). 2012 Apr-Jun;6(2):126-31. doi: 10.4161/fly.20143. Epub 2012 Apr 1.
The Wnt/Wingless (Wg) pathway is an evolutionarily conserved signaling system that is used reiteratively, both spatially and temporally, to control the development of multicellular animals. The stability of cytoplasmic β-catenin/Armadillo, the transcriptional effector of the pathway, is controlled by sequential N-terminal phosphorylation and ubiquitination that targets it for proteasome-mediated degradation. Orthologous members of the Homeodomain-interacting protein kinase family from Drosophila to vertebrates have been implicated in the regulation of Wnt/Wingless signaling. In Drosophila, as a consequence of Hipk activity, cells accumulate stabilized Armadillo that directs the expression of Wg-specific target genes. Hipk promotes the stabilization of Armadillo by inhibiting its ubiquitination (and hence subsequent degradation) by the SCF(Slimb) E3 ubiquitin ligase complex. Vertebrate Hipk2 impedes β-catenin ubiquitination to promote its stability and the Wnt signal in a mechanism that is functionally conserved. Moreover, we describe here that Hipk proteins have a role independent of their effect on β-catenin/Armadillo stability to enhance Wnt/Wingless signaling.
Wnt/Wingless（Wg）信号通路是一种在进化上保守的信号系统，在多细胞动物发育过程中，它在空间和时间上被反复利用来控制发育进程。该信号通路的转录效应因子——细胞质中的β-连环蛋白/犰狳蛋白（Armadillo）的稳定性，受其N端的顺序磷酸化和泛素化调控，使其被蛋白酶体介导降解。从果蝇到脊椎动物，同源结构域相互作用蛋白激酶家族的直系同源成员都参与了Wnt/Wingless信号通路的调控。在果蝇中，由于Hipk的活性，细胞中积累了稳定的犰狳蛋白，从而指导Wg特异性靶基因的表达。Hipk通过抑制SCF（Slimb）E3泛素连接酶复合体对犰狳蛋白的泛素化（进而阻止其后续降解）来促进其稳定性。脊椎动物的Hipk2通过一种功能保守的机制，抑制β-连环蛋白的泛素化，从而促进其稳定性和Wnt信号。此外，我们在此描述，Hipk蛋白在增强Wnt/Wingless信号方面具有独立于其对β-连环蛋白/犰狳蛋白稳定性影响的作用。
