Suppression of casein kinase 1alpha in melanoma cells induces a switch in beta-catenin signaling to promote metastasis.
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.
Sinnberg
Tobias
T
Department of Dermatology, Eberhard-Karls-University Tübingen, Tübingen, Germany.
Menzel
Moritz
M
Kaesler
Susanne
S
Biedermann
Tilo
T
Sauer
Birgit
B
Nahnsen
Sven
S
Schwarz
Michael
M
Garbe
Claus
C
Schittek
Birgit
B
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048128:Casein Kinase Ialpha / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D015536:Down-Regulation; D017353:Gene Deletion; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000502:physiology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
C495270:CTNNB1 protein, human; D051176:beta Catenin; D048128:Casein Kinase Ialpha