Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction.
Signalling by Wnt proteins (Wingless in Drosophila) has diverse roles during embryonic development and in adults, and is implicated in human diseases, including cancer. LDL-receptor-related proteins 5 and 6 (LRP5 and LRP6; Arrow in Drosophila) are key receptors required for transmission of Wnt/beta-catenin signalling in metazoa. Although the role of these receptors in Wnt signalling is well established, their coupling with the cytoplasmic signalling apparatus remains poorly defined. Using a protein modification screen for regulators of LRP6, we describe the identification of Xenopus Casein kinase 1 gamma (CK1gamma), a membrane-bound member of the CK1 family. Gain-of-function and loss-of-function experiments show that CK1gamma is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells. In Xenopus embryos, CK1gamma is required during anterio-posterior patterning to promote posteriorizing Wnt/beta-catenin signalling. CK1gamma is associated with LRP6, which has multiple, modular CK1 phosphorylation sites. Wnt treatment induces the rapid CK1gamma-mediated phosphorylation of these sites within LRP6, which, in turn, promotes the recruitment of the scaffold protein Axin. Our results reveal an evolutionarily conserved mechanism that couples Wnt receptor activation to the cytoplasmic signal transduction apparatus.
Davidson
Gary
G
Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. g.davidson@dkfz-heidelberg.de
Wu
Wei
W
Shen
Jinlong
J
Bilic
Josipa
J
Fenger
Ursula
U
Stannek
Peter
P
Glinka
Andrei
A
Niehrs
Christof
C
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D019521:Body Patterning; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology / Q000235:genetics; D029867:Xenopus Proteins; D051176:beta Catenin / Q000378:metabolism
D060466:Axin Protein; D029721:Drosophila Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D012097:Repressor Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; C474373:arr protein, Drosophila; C555454:axin1 protein, Xenopus; D051176:beta Catenin; D010769:Phosphothreonine; D047389:Casein Kinase I; C479663:gish protein, Drosophila