Suppression of casein kinase 1α in melanoma cells induces a switch in β-catenin signaling to promote metastasis

Abstract

Casein kinase 1 α (CK1α) is a multifunctional Ser/Thr kinase that phosphorylates several substrates. Among those is β-catenin, an important player in cell adhesion and Wnt signaling. Phosphorylation of β-catenin by CK1α at Ser45 is the priming reaction for the proteasomal degradation of β-catenin. Interestingly, aside from this role in β-catenin degradation, very little is known about the expression and functional role of CK1α in tumor cells. Here, we show that CK1α expression in different tumor types is either strongly suppressed or completely lost during tumor progression and that CK1α is a key factor determining β-catenin stability and transcriptional activity in tumor cells. CK1α reexpression in metastatic melanoma cells reduces growth in vitro and metastasis formation in vivo, and induces cell cycle arrest and apoptosis, whereas suppression of CK1α in primary melanoma cells induces invasive tumor growth. Inactivation of CK1α promotes tumor progression by regulating a switch in β-catenin-mediated signaling. These results show that melanoma cells developed an efficient new mechanism to activate the β-catenin signaling pathway and define CK1α as a novel tumor suppressor. ©2010 AACR.