Delineation of a Fat tumor suppressor pathway

Howard Hughes Medical Institute and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Nature Genetics (Impact Factor: 29.35). 11/2006; 38(10):1142-50. DOI: 10.1038/ng1887
Source: PubMed


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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    • "Warts is concentrated near the cell cortex, with an apical bias that overlaps the region of strong App and Dachs accumulation (Figures S10C and S10D). Dachs binds Warts and may thereby regulate the Hippo pathway, accounting for its effects on Ftdependent growth control[4]. As shown here and elsewhere[11], Dachs also modulates the effects of Ft signaling on PCP. "
    Dataset: app paper

    Full-text · Dataset · Jan 2016
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    • "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. "
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    ABSTRACT: The arrival of multicellularity in evolution facilitated cell-cell signaling in conjunction with adhesion. As the ectodomains of cadherins interact with each other directly in trans (as well as in cis), spanning the plasma membrane and associating with multiple other entities, cadherins enable the transduction of "outside-in" or "inside-out" signals. We focus this review on signals that originate from the larger family of cadherins that are inwardly directed to the nucleus, and thus have roles in gene control or nuclear structure-function. The nature of cadherin complexes varies considerably depending on the type of cadherin and its context, and we will address some of these variables for classical cadherins versus other family members. Substantial but still fragmentary progress has been made in understanding the signaling mediators used by varied cadherin complexes to coordinate the state of cell-cell adhesion with gene expression. Evidence that cadherin intracellular binding partners also localize to the nucleus is a major point of interest. In some models, catenins show reduced binding to cadherin cytoplasmic tails favoring their engagement in gene control. When bound, cadherins may serve as stoichiometric competitors of nuclear signals. Cadherins also directly or indirectly affect numerous signaling pathways (e.g., Wnt, receptor tyrosine kinase, Hippo, NFκB, and JAK/STAT), enabling cell-cell contacts to touch upon multiple biological outcomes in embryonic development and tissue homeostasis. © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Current Topics in Developmental Biology
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    • "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). "
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    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 yes-associated protein (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 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.
    Full-text · Article · Feb 2014 · Molecular Biology and Evolution
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