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  • Introduction br CK in the Regulation of Hh Pathway

    2020-02-11

    Introduction
    CK1 in the Regulation of Hh Pathway CK1 was initially identified as a negative regulator of Hh signaling at the level of transcription factor Ci by genetic studies in Drosophila and genome-wide RNAi screen in Drosophila cultured GNE-617 (Jia et al., 2005, Lum et al., 2003, Price and Kalderon, 2002). Overexpression of a dominant negative form of CK1ɛ resulted in an ectopic expression of an Hh target gene decapentaplegic (dpp) in wing imaginal discs and duplication of adult wings (Jia et al., 2005), phenocopying ectopic Hh expression (Basler & Struhl, 1994). However, further genetic study revealed that CK1 also plays a positive role in the Hh pathway at the level of Smo (Jia, Tong, Wang, Luo, & Jiang, 2004). A kinome-wide RNAi screen identified CK1α as a positive regulator of Hh signaling in mammalian cultured cells (Evangelista et al., 2008), and a subsequent study demonstrated that CK1α regulates Hh signaling by phosphorylating and activating Smo (Chen et al., 2011). In Drosophila, CK1 also exerts its positive role by phosphorylating Ci to stabilize the CiA and by phosphorylating fused (Fu) to promote its activation (Shi et al., 2014, Zhou and Kalderon, 2011). Hence CK1 plays a dual role in Hh signaling and acts at multiple levels.
    CK1 in Wnt Signaling Similar to its role in the Hh pathway, CK1 also plays both positive and negative roles in the Wnt pathway by phosphorylating different pathway components. The first indication that CK1 family kinase regulates Wnt signaling is that injection of CK1ɛ mRNA into the ventral side of Xenopus embryos led to dorsalization and axial duplication similar to injection of Wnts (Peters et al., 1999, Sakanaka et al., 1999). It was further shown that CK1ɛ forms a complex with Disheveled (Dvl) and Axin and positively regulates Wnt signaling by phosphorylating Dvl on multiple sites (McKay et al., 2001, Peters et al., 1999, Sakanaka et al., 1999). However, the physiological relevance of Dvl phosphorylation by CK1 has not been clearly established (Penton et al., 2002, Strutt et al., 2006, Yanfeng et al., 2011). Other CK1 family members including CK1α and CK1γ have also been implicated in Wnt signaling (see later). Although CK1ɛ and CK1γ mainly play a positive role in Wnt signaling through their influence on LRP6 and Dvl, whereas CK1α mainly plays a negative role through its role in the regulation of β-catenin degradation, a genetic study in Drosophila also reveals a negative role for CK1ɛ and a positive role for CK1α in a genetic sensitized background (Zhang, Jia, et al., 2006).
    Regulation of CK1 in Hh and Wnt Signaling The involvement of CK1 in both Hh and Wnt signal transduction pathways and the findings that CK1 regulates each pathway at multiple levels to exert both positive and negative influence have raised import questions of how phosphorylation of CK1 substrates is regulated and how Hh and Wnt signaling achieve pathway specificity despite being regulated by a similar set of kinases. A prominent feature of Hh and Wnt signaling is that the kinases and their substrates are present in large protein complexes organized by pathway-specific scaffolding proteins (Fig. 2). In the Hh pathway, Ci and its kinases PKA, CK1, and GSK3 are present in protein complexes organized by Cos2 and Fu (Chen and Jiang, 2013, Zhang et al., 2005). Similarly in the Wnt pathway, β-catenin and its kinases CK1 and GSK3 form a complex scaffolded by Axin and APC (MacDonald et al., 2009). Therefore, to achieve pathway specificity, Hh and Wnt regulate different pools of kinases by eliciting interaction between their receptor complexes and the pathway-specific scaffold proteins, i.e., Smo/Cos2 interaction in the Hh pathway and LRP6/Axin interaction in the Wnt pathway (Jia et al., 2003, Jiang and Hui, 2008, MacDonald et al., 2009, Tamai et al., 2004). In other words, Hh and Wnt signaling are regulated by specific pool of kinases that are compartmentalized with their pathway effectors.