TitleUnderstanding the molecular mechanism of the fat signaling pathway in Drosophila melanogaster
NameFeng, YongQiang (author), Edery, Isaac (chair), Padgett, Richard (internal member), Steward, Ruth (internal member), Irvine, Kenneth (internal member), Matise, Michael (outside member), Rutgers University, Graduate School - New Brunswick,
SubjectCell and Developmental Biology,
Cellular signal transduction,
DescriptionFat is an atypical cadherin and regulates planar cell polarity (PCP) and imaginal disc growth. The Golgi kinase Four-jointed modulates the interaction of Fat and its potential ligand Dachsous and an unconvential myosin Dachs mediates nearly all Fat functions. The Hippo tumor suppressor pathway was demonstrated to regulate growth and cell death through the kinase Warts and transcription factor Yorkie. Genetically, the Hippo pathway is downstream of Fat, Dachs and the FERM-domain protein Expanded. The molecular basis was unknown how Fat interacts with Expanded and how Fat and Dachs regulate the Hippo pathway.
We found that Fat regulates Warts stability in a Dachs-dependent manner. Expanded and other tumor suppressors inluding Hippo, Mats and Salvador do not affect Warts levels, suggesting a distinct mechanism in regulating Warts. A casein kinase I δ/ε mutant, dco3 also destabilizes Warts, and genetically is upstream of dachs. The regulation of Warts by Fat and Expanded via different mechanisms was further validated by the additive effects of fat and expanded on imaginal disc growth and development. Mutation of fat also influences Expanded stability or subcellular localization through Dachs, indicating a crosstalk between Fat pathway and Expanded.
The significance of Warts in Fat and Expanded functions was demonstrated by our observation that mutations in either expanded or fat were rescued to viability by overexpressing Warts, indicating that reported effects on endocytosis or other pathways are not essential. These rescue experiments also separate the transcriptional from the PCP branches of Fat signaling and reveal that Expanded does not directly affect PCP.
We found that Fat is subject to a constitutive proteolytic processing, such that most or all cell surface Fat comprises a heterodimer of stably associated N- and C-terminal fragments. The cytoplasmic domain of Fat is phosphorylated, which is promoted by Dachsous. Dco is required for Fat signaling, and is able to phosphorylate the Fat intracellular domain in cultured cells, and is required for normal Fat phosphorylation in vivo. dco3 mutant affects Fat’s influence on growth and gene expression, but not its influence on PCP, suggesting separated growth and PCP pathways from Fat.
NoteIncludes bibliographical references (p. 185-197)
Noteby YongQiang Feng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work