Unwinding the Wnt action of casein kinase 1

Abstract

npgThe casein kinase 1 (CK1) family, a major intracellular serine/threonine kinase, is implicated in multiple pathways; however, understanding its regulation has proven challenging. A recent study published in Science identifying allosteric activation of CK1 by the DEAD-box RNA helicase DDX3 expands our understanding of the control of this abundant kinase family.The human CK1 protein kinase family is encoded by six genes (α, γ1, γ2, γ3, δ, and ɛ) and regulates diverse biochemical processes including hedgehog signaling, circadian rhythms and the p53 tumor suppression [reviewed in 1]. In the Wnt/β-catenin pathway, all CK1 family members are involved, each with a distinct role. To carry out their functions, CK1 family members achieve specificity by several mechanisms, but how their kinase activity is regulated has been less clear. Here, we discuss the findings of the Niehrs lab [2] in the context of what is known about CK1 control in the Wnt pathway.CK1γ proteins are membrane bound due to C-terminal S-palmitoylation and phosphorylate the Wnt co-receptor LRP5/6 in the presence of Wnts and Disheveled to activate the pathway [3,4]. One mechanism of activation may be via 'priming' by upstream phosphorylation of LRP5/6, a common characteristic of CK1 substrate recognition [5]. CK1δ and CK1ε bind to and phosphorylate Disheveled, an activity regulated by Wnt signaling and protein phosphatases [6,7]. CK1α interacts with and phosphorylates APC, Axin and Ser45 of β-catenin in an apparently unregulated reaction. The CK1α-catalyzed phosphorylation

Casein kinase 1‐epsilon deletion increases mu opioid receptor‐dependent behaviors and binge eating1

“…GSK3B was identified as a top PPI hub protein via analysis with the Enrichr tool (Table 1) (Kuleshov et al 2016). Csnk1e is a positive regulator of the Wnt signaling pathway (Sakanaka et al 1999) that phosphorylates substrates such as disheveled, axin and Tcf-3 (Cheong & Virshup 2011;Yim & Virshup 2013). Furthermore, GSK3B in the hypothalamus has been shown to play a crucial role in regulating food intake and glucose metabolism in leptin-deficient mice (Benzler et al 2012) as well as opioid-induced tolerance (Parkitna et al 2006) and opioidinduced apoptosis (Xie et al 2010) and mu opioid receptor agonist-induced membrane expression and trafficking of glutamate receptors during opioid-induced hyperalgesia Yuan et al 2013;Zhang et al 2014).…”

Wnt ligand–dependent activation of the negative feedback regulator Nkd1

“…Although there are several kinases that function during Wnt signaling, their activation is unknown, and these kinases may be constitutively active or regulated independently of Wnt ligand–mediated activation of the receptor ( Cruciat et al. , 2013 ; Yim and Virshup, 2013 ). One model that has been suggested is that Nkd/Nkd1 simply sequesters Dsh/Dvl, allowing reactivation of the Arm/β-catenin destruction complex ( Rousset et al.…”

Moliere

“…More recently, DDX3 activity was found to be involved cancer development and progression mainly through regulation of the Wnt signaling pathway [13, 50] and associated regulation of Cell-cell and Cell-matrix adhesion, tumor cells invasion, and metastasis [12, 43, 48, 24]. Currently, DDX3 is an established target for anti-tumor drug development [10, 37, 11] and represents a case for repurposing target anti-viral drugs into the application area of anti-tumor therapy.…”