Abstract
Casein kinase 1 alpha (CK1alpha) is a multifunctional Ser/Thr kinase that phosphorylates several substrates. Among those is beta-catenin, an important player in cell adhesion and Wnt signaling. Phosphorylation of beta-catenin by CK1alpha at Ser45 is the priming reaction for the proteasomal degradation of beta-catenin. Interestingly, aside from this role in beta-catenin degradation, very little is known about the expression and functional role of CK1alpha in tumor cells. Here, we show that CK1alpha expression in different tumor types is either strongly suppressed or completely lost during tumor progression and that CK1alpha is a key factor determining beta-catenin stability and transcriptional activity in tumor cells. CK1alpha reexpression in metastatic melanoma cells reduces growth in vitro and metastasis formation in vivo, and induces cell cycle arrest and apoptosis, whereas suppression of CK1alpha in primary melanoma cells induces invasive tumor growth. Inactivation of CK1alpha promotes tumor progression by regulating a switch in beta-catenin-mediated signaling. These results show that melanoma cells developed an efficient new mechanism to activate the beta-catenin signaling pathway and define CK1alpha as a novel tumor suppressor.
Highlights
The casein kinase 1 (CK1) family of serine/threonine protein kinases—ubiquitously found in eukaryotes—phosphorylates a large number of cellular proteins [1,2,3,4]
By screening cDNA libraries of primary and metastatic melanoma tissues, we identified Casein kinase 1 α (CK1α) as a gene that is downregulated in metastatic compared with primary melanoma cells
We found RNA and protein expression of CK1α to be significantly reduced in metastatic compared with nonmetastatic melanoma cells, whereas β-catenin expression is strongly increased and the protein preferentially localized in the nucleus in metastatic melanoma cells (Fig. 1A)
Summary
The casein kinase 1 (CK1) family of serine/threonine protein kinases—ubiquitously found in eukaryotes—phosphorylates a large number of cellular proteins [1,2,3,4]. Seven CK1 family members have been described in vertebrates: CK1α, CK1β, CK1γ1, CK1γ2, CK1γ3, CK1δ, and CK1ε [4, 5]. The CK1 protein kinases are involved in several important cellular processes, such as cell division, DNA repair, circadian rhythms, nuclear import, chromosome segregation, spindle formation, and the development of neurodegenerative diseases [4, 5]. It has been shown that CK1 family members play a role in regulating Wnt and Hedgehog signaling [1, 5]. CK1 isoforms were identified as positive and negative regulators of the Wnt pathway [4]. It was described that CK1α and CK1ε phosphorylate mem-
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