title: Frizzled receptors activate a novel JNK-dependent pathway that may lead to apoptosis.
abstract: Extracellular Wnt ligands and their receptors of the Frizzled family control cell fate, proliferation, and polarity during metazoan development. Frizzled signaling modulates target gene expression through a beta-catenin-dependent pathway, functions to establish planar cell polarity in Drosophila epithelia, and activates convergent extension movements and intracellular Ca(2+) signaling in frog and fish embryos. Here, we report that a Frizzled receptor, Xenopus Frizzled 8 (Xfz8), activates c-Jun N-terminal kinases (JNK) and triggers rapid apoptotic cell death in gastrulating Xenopus embryos. This activity of Xfz8 required the cytoplasmic tail of the receptor and was blocked by a dominant inhibitor of JNK. Moreover, the cytoplasmic tail of Xfz8 targeted to the membrane was sufficient for activation of JNK and apoptosis. The apoptotic signaling was shared by a specific subset of Frizzled receptors, was inhibited by Wnt5a, and occurred in a Dishevelled- and T cell factor (TCF)-independent manner. Thus, our experiments identify a novel Frizzled-dependent signaling pathway, which involves JNK and differs from the beta-catenin-dependent and convergent extension pathways.
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School and Molecular Medicine Unit, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Lisovsky
authors.forename: Keiji
authors.initials: K
authors.lastname: Itoh
authors.forename: Sergei Y
authors.initials: SY
authors.lastname: Sokol
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000201:enzymology; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D009154:Mutation; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014981:Xenopus / Q000196:embryology* / Q000378:metabolism; D029867:Xenopus Proteins / Q000502:physiology
chemical_list: C113865:FZD8 protein, Xenopus; D011956:Receptors, Cell Surface; D029867:Xenopus Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases