title: Regulation of wingless signaling by the CKI family in Drosophila limb development.
abstract: The Wingless (Wg)/Wnt signaling pathway regulates a myriad of developmental processes and its malfunction leads to human disorders including cancer. Recent studies suggest that casein kinase I (CKI) family members play pivotal roles in the Wg/Wnt pathway. However, genetic evidence for the involvement of CKI family members in physiological Wg/Wnt signaling events is lacking. In addition, there are conflicting reports regarding whether a given CKI family member functions as a positive or negative regulator of the pathway. Here we examine the roles of seven CKI family members in Wg signaling during Drosophila limb development. We find that increased CKIepsilon stimulates whereas dominant-negative or a null CKIepsilon mutation inhibits Wg signaling. In contrast, inactivation of CKIalpha by RNA interference (RNAi) leads to ectopic Wg signaling. Interestingly, hypomorphic CKIepsilon mutations synergize with CKIalpha RNAi to induce ectopic Wg signaling, revealing a negative role for CKIepsilon. Conversely, CKIalpha RNAi enhances the loss-of-Wg phenotypes caused by CKIepsilon null mutation, suggesting a positive role for CKIalpha. While none of the other five CKI isoforms can substitute for CKIalpha in its inhibitory role in the Wg pathway, several CKI isoforms including CG12147 exhibit a positive role based on overexpression. Moreover, loss of Gilgamesh (Gish)/CKIgamma attenuates Wg signaling activity. Finally, we provide evidence that several CKI isoforms including CKIalpha and Gish/CKIgamma can phosphorylate the Wg coreceptor Arrow (Arr), which may account, at least in part, for their positive roles in the Wg pathway.
authors.affiliation: Center for Developmental Biology, Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Jianhang
authors.initials: J
authors.lastname: Jia
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Amanai
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wharton
authors.forename: Jin
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000818:Animals; D048149:Casein Kinase 1 epsilon / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism; D047389:Casein Kinase I / Q000737:chemistry / Q000378:metabolism*; D048128:Casein Kinase Ialpha / Q000737:chemistry / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000378:metabolism*; D005121:Extremities / Q000196:embryology*; D005799:Genes, Dominant / Q000235:genetics; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D014921:Wings, Animal / Q000166:cytology; D051155:Wnt1 Protein; D014981:Xenopus
chemical_list: D029721:Drosophila Proteins; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D051155:Wnt1 Protein; C474373:arr protein, Drosophila; C074622:wg protein, Drosophila; D048149:Casein Kinase 1 epsilon; D047389:Casein Kinase I; D048128:Casein Kinase Ialpha; C479663:gish protein, Drosophila