Cell cycle control of wnt receptor activation.
Low-density lipoprotein receptor related proteins 5 and 6 (LRP5/6) are transmembrane receptors that initiate Wnt/beta-catenin signaling. Phosphorylation of PPPSP motifs in the LRP6 cytoplasmic domain is crucial for signal transduction. Using a kinome-wide RNAi screen, we show that PPPSP phosphorylation requires the Drosophila Cyclin-dependent kinase (CDK) L63. L63 and its vertebrate homolog PFTK are regulated by the membrane tethered G2/M Cyclin, Cyclin Y, which mediates binding to and phosphorylation of LRP6. As a consequence, LRP6 phosphorylation and Wnt/beta-catenin signaling are under cell cycle control and peak at G2/M phase; knockdown of the mitotic regulator CDC25/string, which results in G2/M arrest, enhances Wnt signaling in a Cyclin Y-dependent manner. In Xenopus embryos, Cyclin Y is required in vivo for LRP6 phosphorylation, maternal Wnt signaling, and Wnt-dependent anteroposterior embryonic patterning. G2/M priming of LRP6 by a Cyclin/CDK complex introduces an unexpected new layer of regulation of Wnt signaling.
Davidson
Gary
G
Division of Molecular Embryology, Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Hermann von Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany. gary.davidson@kit.edu
Shen
Jinlong
J
Huang
Ya-Lin
YL
Su
Yi
Y
Karaulanov
Emil
E
Bartscherer
Kerstin
K
Hassler
Christine
C
Stannek
Peter
P
Boutros
Michael
M
Niehrs
Christof
C
D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D016213:Cyclins / Q000378:metabolism; D004330:Drosophila; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010766:Phosphorylation; D040901:Proteomics; D011973:Receptors, LDL / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D014982:Xenopus laevis
D016213:Cyclins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011973:Receptors, LDL; D051153:Wnt Proteins