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.
"Author's personal copy binding interface (Graham, Weaver, Mao, Kimelman, & Xu, 2000; Huber & Weis, 2001), where the cadherin:β-catenin interaction is of higher affinity than that of TCF:β-catenin (Choi, Huber, & Weis, 2006), these data collectively show how cadherins can, in principle, function as stoichiometric inhibitors of β-catenin/TCF (etc.) signaling. "
"4B; supplementary table S1, Supplementary Material online). Validating our approach, this signature comprised 213 commonly upregulated targets that included almost all previously known Yki target genes (cyclin E [Tapon et al. 2002], expanded [Hamaratoglu et al. 2006], e2f1 [Goulev et al. 2008], wingless [Cho et al. 2006], dally [Baena-Lopez et al. 2008], kibra [Genevet et al. 2010], and vein [Zhang, Ji, et al. 2009]), along with 258 commonly downregulated factors (fig. 4B). "
[Show abstract][Hide abstract] ABSTRACT: Throughout Metazoa, developmental processes are controlled by a surprisingly limited number of conserved signaling pathways. Precisely how these signaling cassettes were assembled in early animal evolution remains poorly understood, as do the molecular transitions that potentiated the acquisition of their myriad developmental functions. Here we analyze the molecular evolution of the proto-oncogene YAP/Yorkie, a key effector of the Hippo signaling pathway that controls organ size in both Drosophila and mammals. Based on heterologous functional analysis of evolutionarily distant Yap/Yorkie orthologs, we demonstrate that a structurally distinct interaction interface between Yap/Yorkie and its partner TEAD/Scalloped became fixed in the eumetazoan common ancestor. We then combine transcriptional profiling of tissues expressing phylogenetically diverse forms of Yap/Yorkie with ChIP-seq validation in order to identify a common downstream gene expression program underlying the control of tissue growth in Drosophila. Intriguingly, a subset of the newly-identified Yorkie target genes are also induced by Yap in mammalian tissues, thus revealing a conserved Yap-dependent gene expression signature likely to mediate organ size control throughout bilaterian animals. Combined, these experiments provide new mechanistic insights while revealing the ancient evolutionary history of Hippo signaling.
"also of the EGFR and InR pathways ( Greaves et al . , 1999 ; Rebay et al . , 2000 ; Huang and Rubin , 2000 ; Guichard et al . , 2002 ; Mahoney et al . , 2006 ) . More recently , mosaic screens in adult structures of the fly uncovered the SWH pathway , because of its contribution to the regulation of cell proliferation , competition and apoptosis ( Cho et al . , 2006 ; Harvey and Tapon , 2007 Tyler et al . , 2007 ) ."
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