CKIepsilon/discs overgrown promotes both Wnt-Fz/beta-catenin and Fz/PCP signaling in Drosophila.
The related Wnt-Frizzled(Fz)/beta-catenin and Fz/planar cell polarity (PCP) pathways are essential for the regulation of numerous developmental processes and are deregulated in many human diseases. Both pathways require members of the Dishevelled (Dsh or Dvl) family of cytoplasmic factors for signal transduction downstream of the Fz receptors. Dsh family members have been studied extensively, but their activation and regulation remains largely unknown. In particular, very little is known about how Dsh differentially signals to the two pathways. Recent work in cell culture has suggested that phosphorylation of Dsh by Casein Kinase I epsilon (CKIepsilon) may act as a molecular "switch," promoting Wnt/beta-catenin while inhibiting Fz/PCP signaling. Here, we demonstrate in vivo in Drosophila through a series of loss-of-function and coexpression assays that CKIepsilon acts positively for signaling in both pathways, rather than as a switch. Our data suggest that the kinase activity of CKIepsilon is required for peak levels of Wnt/beta-catenin signaling. In contrast, CKIepsilon is a mandatory signaling factor in the Fz/PCP pathway, possibly through a kinase-independent mechanism. Furthermore, we have identified the primary kinase target residue of CKIepsilon on Dsh. Thus, our data suggest that CKIepsilon modulates Wnt/beta-catenin and Fz/PCP signaling pathways via kinase-dependent and -independent mechanisms.
Klein
Thomas J
TJ
Department of Molecular, Cell, and Developmental Biology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, New York 10029, USA.
Jenny
Andreas
A
Djiane
Alexandre
A
Mlodzik
Marek
M
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D048149:Casein Kinase 1 epsilon / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016764:Cell Polarity / Q000235:genetics; D000072261:Dishevelled Proteins; D004330:Drosophila / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D051157:Frizzled Receptors / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D016415:Sequence Alignment; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014921:Wings, Animal / Q000033:anatomy & histology / Q000254:growth & development / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051155:Wnt1 Protein; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D051157:Frizzled Receptors; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin; C113519:dco protein, Drosophila; C000606588:dsh protein, Drosophila; C058784:fz protein, Drosophila; C074622:wg protein, Drosophila; D012694:Serine; D048149:Casein Kinase 1 epsilon