Suppression of Casein Kinase 1α in Melanoma Cells Induces a Switch in β-Catenin Signaling to Promote Metastasis

Casein kinase 1 alpha (CK1 alpha) 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 CK1 alpha 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 CK1a in tumor cells. Here, we show that CK1a expression in different tumor types is either strongly suppressed or completely lost during tumor progression and that CK1 alpha is a key factor determining beta-catenin stability and transcriptional activity in tumor cells. CK1 alpha reexpression in metastatic melanoma cells reduces growth in vitro and metastasis formation in vivo, and induces cell cycle arrest and apoptosis, whereas suppression of CK1 alpha in primary melanoma cells induces invasive tumor growth. Inactivation of CK1 alpha 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 CK1 alpha as a novel tumor suppressor. Cancer Res; 70(17); 6999-7009. (C) 2010 AACR.