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      Kibra Is a Regulator of the Salvador/Warts/Hippo Signaling Network

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          Summary

          The Salvador (Sav)/Warts (Wts)/Hippo (Hpo) (SWH) network controls tissue growth by inhibiting cell proliferation and promoting apoptosis. The core of the pathway consists of a MST and LATS family kinase cascade that ultimately phosphorylates and inactivates the YAP/Yorkie (Yki) transcription coactivator. The FERM domain proteins Merlin (Mer) and Expanded (Ex) represent one mode of upstream regulation controlling pathway activity. Here, we identify Kibra as a member of the SWH network. Kibra, which colocalizes and associates with Mer and Ex, also promotes the Mer/Ex association. Furthermore, the Kibra/Mer association is conserved in human cells. Finally, Kibra complexes with Wts and kibra depletion in tissue culture cells induces a marked reduction in Yki phosphorylation without affecting the Yki/Wts interaction. We suggest that Kibra is part of an apical scaffold that promotes SWH pathway activity.

          Highlights

          ► The Salvador/Hippo/Warts network restricts tissue size ► We identify the scaffold protein Kibra as a SWH upstream regulator ► Kibra promotes SWH activity by complexing with multiple pathway members

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          Most cited references24

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          Genome-wide RNAi analysis of growth and viability in Drosophila cells.

          A crucial aim upon completion of whole genome sequences is the functional analysis of all predicted genes. We have applied a high-throughput RNA-interference (RNAi) screen of 19,470 double-stranded (ds) RNAs in cultured cells to characterize the function of nearly all (91%) predicted Drosophila genes in cell growth and viability. We found 438 dsRNAs that identified essential genes, among which 80% lacked mutant alleles. A quantitative assay of cell number was applied to identify genes of known and uncharacterized functions. In particular, we demonstrate a role for the homolog of a mammalian acute myeloid leukemia gene (AML1) in cell survival. Such a systematic screen for cell phenotypes, such as cell viability, can thus be effective in characterizing functionally related genes on a genome-wide scale.
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            The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network.

            Intense research over the past four years has led to the discovery and characterization of a novel signalling network, known as the Salvador-Warts-Hippo (SWH) pathway, involved in tissue growth control in Drosophila melanogaster. At present, eleven proteins have been implicated as members of this pathway, and several downstream effector genes have been characterized. The importance of this pathway is emphasized by its evolutionary conservation, and by increasing evidence that its deregulation occurs in human tumours. Here, we review the main findings from Drosophila and the implications that these have for tumorigenesis in mammals.
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              Filling out the Hippo pathway.

              How cell numbers are controlled during organ development is a problem that is still in need of answers. Recent studies in Drosophila melanogaster have delineated a novel signalling pathway, the Hippo pathway, which has an important role in restraining cell proliferation and promoting apoptosis in differentiating epithelial cells. Much like cancer cells, cells that contain mutations for components of the Hippo pathway proliferate inappropriately and have a competitive edge in genetically mosaic tissues. Although poorly characterized in mammals, several components of the Hippo pathway seem to be tumour suppressors in humans.
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                Author and article information

                Journal
                Dev Cell
                Dev. Cell
                Developmental Cell
                Cell Press
                1534-5807
                1878-1551
                16 February 2010
                16 February 2010
                : 18
                : 2-3
                : 300-308
                Affiliations
                [1 ]Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
                [2 ]Epithelial Biology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
                Author notes
                []Corresponding author barry.thompson@ 123456cancer.org.uk
                [∗∗ ]Corresponding author nicolas.tapon@ 123456cancer.org.uk
                Article
                DEVCEL1830
                10.1016/j.devcel.2009.12.011
                2845807
                20159599
                98b69c8f-2109-4aeb-8339-652aa87089d6
                © 2010 ELL & Excerpta Medica.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 27 May 2009
                : 20 October 2009
                : 24 December 2009
                Categories
                Short Article

                Developmental biology
                signaling,cellbio,devbio
                Developmental biology
                signaling, cellbio, devbio

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