Published online: 17 September 2006; Corrected online: 16 October 2006 | doi:10.1038/ng1887
Delineation of a Fat tumor suppressor pathwayEunjoo Cho1, 4, Yongqiang Feng1, 4, Cordelia Rauskolb2, Sushmita Maitra3, Rick Fehon3 & Kenneth D Irvine11
Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA. 2
Waksman Institute, Rutgers, The State University of New Jersey, Piscataway New Jersey 08854, USA. 3
Department of Molecular Genetics and Cell Biology, 920 E. 58th St, University of Chicago, Chicago, Illinois 60637, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Kenneth D Irvine irvine@waksman.rutgers.edu Recent studies in Drosophila melanogaster of the protocadherins Dachsous and Fat suggest that they act as ligand and receptor, respectively, for an intercellular signaling pathway that influences tissue polarity, growth and gene expression, but the basis for signaling downstream of Fat has remained unclear. Here, we characterize functional relationships among D. melanogaster tumor suppressors and identify the kinases Discs overgrown and Warts as components of a Fat signaling pathway. fat, discs overgrown and warts regulate a common set of downstream genes in multiple tissues. Genetic experiments position the action of discs overgrown upstream of the Fat pathway component dachs, whereas warts acts downstream of dachs. Warts protein coprecipitates with Dachs, and Warts protein levels are influenced by fat, dachs and discs overgrown in vivo, consistent with its placement as a downstream component of the pathway. The tumor suppressors Merlin, expanded, hippo, salvador and mob as tumor suppressor also share multiple Fat pathway phenotypes but regulate Warts activity independently. Our results functionally link what had been four disparate groups of D. melanogaster tumor suppressors, establish a basic framework for Fat signaling from receptor to transcription factor and implicate Warts as an integrator of multiple growth control signals.
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