title: Signal transduction by the Fat cytoplasmic domain.
abstract: The large atypical cadherin Fat is a receptor for both Hippo and planar cell polarity (PCP) pathways. Here we investigate the molecular basis for signal transduction downstream of Fat by creating targeted alterations within a genomic construct that contains the entire fat locus, and by monitoring and manipulating the membrane localization of the Fat pathway component Dachs. We establish that the human Fat homolog FAT4 lacks the ability to transduce Hippo signaling in Drosophila, but can transduce Drosophila PCP signaling. Targeted deletion of conserved motifs identifies a four amino acid C-terminal motif that is essential for aspects of Fat-mediated PCP, and other internal motifs that contribute to Fat-Hippo signaling. Fat-Hippo signaling requires the Drosophila Casein kinase 1ε encoded by discs overgrown (Dco), and we characterize candidate Dco phosphorylation sites in the Fat intracellular domain (ICD), the mutation of which impairs Fat-Hippo signaling. Through characterization of Dachs localization and directed membrane targeting of Dachs, we show that localization of Dachs influences both the Hippo and PCP pathways. Our results identify a conservation of Fat-PCP signaling mechanisms, establish distinct functions for different regions of the Fat ICD, support the correlation of Fat ICD phosphorylation with Fat-Hippo signaling, and confirm the importance of Dachs membrane localization to downstream signaling pathways.
authors: Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers The State University of New Jersey, Piscataway, NJ 08854, USA. irvine@waksman.rutgers.edu
authors: Guohui
authors: G
authors: Pan
authors: Yongqiang
authors: Y
authors: Feng
authors: Abhijit A
authors: AA
authors: Ambegaonkar
authors: Gongping
authors: G
authors: Sun
authors: Matthew
authors: M
authors: Huff
authors: Cordelia
authors: C
authors: Rauskolb
authors: Kenneth D
authors: KD
authors: Irvine
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D048149:Casein Kinase 1 epsilon / Q000235:genetics; D004330:Drosophila / Q000196:embryology* / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D006652:Histological Techniques; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009218:Myosins / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D015820:Cadherins; D048149:Casein Kinase 1 epsilon; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009218:Myosins; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C534294:FAT4 protein, human; C492999:dachs protein, Drosophila; C113519:dco protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases