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

Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Developmental Cell (Impact Factor: 9.71). 02/2010; 18(2):300-8. DOI: 10.1016/j.devcel.2009.12.011
Source: PubMed


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.

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Available from: Michael C Wehr, Oct 23, 2014
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    • " ( 1 : 200 , Z378B , Promega ) , rabbit anti - β - galactosidase ( 1 : 1000 , 55976 , Cappel ) , rabbit anti - activated caspase 3 ( 1 : 150 , 9661L , Cell Signaling ) , rat anti - DE - Cad ( 1 : 50 , CAD2 , DSHB ) , rabbit anti - Ex ( 1 : 200 , a gift from A . Laughon , University of Wisconsin , Madison , WI , USA ) and rat anti - Yki ( 1 : 200 , Genevet et al . , 2010 ) . Rhodamine - conjugated phalloidin ( Sigma ) was used at a concentration of 0 . 3 μM . Fluorescently labeled secondary antibodies were from Jackson Immunoresearch ( 1 : 200 ) ."
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    ABSTRACT: The Drosophila transcriptional co-activator protein Yorkie and its vertebrate orthologs YAP and TAZ are potent oncogenes, whose activity is normally kept in check by the upstream Hippo kinase module. Upon its translocation into the nucleus, Yorkie forms complexes with several tissue-specific DNA-binding partners, which help to define the tissue-specific target genes of Yorkie. In the progenitor cells of the eye imaginal disc, the DNA-binding transcription factor Homothorax is required for Yorkie-promoted proliferation and survival through regulation of the bantam microRNA (miRNA). The transit from proliferating progenitors to cell cycle quiescent precursors is associated with the progressive loss of Homothorax and gain of Dachshund, a nuclear protein related to the Sno/Ski family of co-repressors. We have identified Dachshund as an inhibitor of Homothorax-Yorkie-mediated cell proliferation. Loss of dachshund induces Yorkie-dependent tissue overgrowth. Conversely, overexpressing dachshund inhibits tissue growth, prevents Yorkie or Homothorax-mediated cell proliferation of disc epithelia and restricts the transcriptional activity of the Yorkie-Homothorax complex on the bantam enhancer in Drosophila cells. In addition, Dachshund collaborates with the Decapentaplegic receptor Thickveins to repress Homothorax and Cyclin B expression in quiescent precursors. The antagonistic roles of Homothorax and Dachshund in Yorkie activity, together with their mutual repression, ensure that progenitor and precursor cells are under distinct proliferation regimes. Based on the crucial role of the human dachshund homolog DACH1 in tumorigenesis, our work suggests that DACH1 might prevent cellular transformation by limiting the oncogenic activity of YAP and/or TAZ. © 2015. Published by The Company of Biologists Ltd.
    Development 03/2015; 142(8). DOI:10.1242/dev.113340 · 6.46 Impact Factor
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    • "Two WW domain-containing proteins, Salvador (SAV) and yki (YAP in mammals), contribute to the core of Hippo pathway. Furthermore, studies recently found that several WWCPs including kibra (Baumgartner et al. 2010; Genevet et al. 2010; Moleirinho et al. 2012), WBP-2 (Chan et al. 2011b) and WWP1 E3 ligase (Yeung et al. 2013) involved in Hippo pathway regulation. Due to the conservation of Hippo signaling pathway, we assume that these findings could also be applied to silkworm. "
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    ABSTRACT: WW domains are protein modules that mediate protein-protein interactions through recognition of proline-rich peptide motifs and phosphorylated serine/threonine-proline sites. WW domains are found in many different structural and signaling proteins that are involved in a variety of cellular processes. WW domain-containing proteins (WWCPs) and complexes have been implicated in major human diseases including cancer as well as in major signaling cascades such as the Hippo tumor suppressor pathway, making them targets for new diagnostics and therapeutics. There are a number of reports about the WWCPs in different species, but systematic analysis of the WWCP genes and its ligands is still lacking in silkworm and the other organisms. In this study, WWCP genes and PY motif-containing proteins have been identified and analyzed in 56 species including silkworm. Whole-genome screening of B. mori identified thirty-three proteins with thirty-nine WW domains located on thirteen chromosomes. In the 39 silkworm WW domains, 15 domains belong to the Group I WW domain; 14 domains were in Group II/III, 9 domains derived from 8 silkworm WWCPs could not be classified into any group, and Group IV contains only one WW domain. Based on gene annotation, silkworm WWCP genes have functions in multi-biology processes. A detailed list of WWCPs from the other 55 species was sorted in this work. In 14,623 silkworm predicted proteins, nearly 18 % contained PY motif, nearly 30 % contained various motifs totally that could be recognized by WW domains. Gene Ontology and KEGG analysis revealed that dozens of WW domain-binding proteins are involved in Wnt, Hedgehog, Notch, mTOR, EGF and Jak-STAT signaling pathway. Tissue expression patterns of WWCP genes and potential WWCP-binding protein genes on the third day of the fifth instar (L5D3) were examined by microarray analysis. Tissue expression profile analysis found that several WWCP genes and poly-proline or PY motif-containing protein genes took tissue- or gender-dependent expression manner in silkworms. We further analyzed WWCPs and PY motif-containing proteins in representative organisms of invertebrates and vertebrates. The results showed that there are no less than 16 and up to 29 WWCPs in insects, the average is 22. The number of WW domains in insects is no less than 19, and up to 47, the average is 36. In vertebrates, excluding the Hydrobiontes, the number of WWCPs is no less than 34 and up to 49, the average is 43. The number of WW domains in vertebrates is no less than 56 and up to 85, the average is 73. Phylogenetic analysis revealed that most homologous genes of the WWCP subfamily in vertebrates were duplicated during evolution and functions diverged. Nearly 1,000 PY motif-containing protein genes were found in insect genomes and nearly 2,000 genes in vertebrates. The different distributions of WWCP genes and PY motif-containing protein genes in different species revealed a possible positive correlation with organism complexity. In conclusion, this comprehensive bio-information analysis of WWCPs and its binding ligands would provide rich fundamental knowledge and useful information for further exploration of the function of the WW domain-containing proteins not only in silkworm, but also in other species.
    Molecular Genetics and Genomics 11/2014; 290(3). DOI:10.1007/s00438-014-0958-6 · 2.73 Impact Factor
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    • "Overexpression of all three human WWC proteins showed similar (although weaker) effects as DmKibra: a rough eye phenotype as well as a reduction of the posterior wing size compartment (fig. 6; Baumgartner et al. 2010; Genevet et al. 2010; Yu et al. 2010). These observations indicate that the ability of the WWC proteins to modulate the Hippo pathway, to inhibit cell proliferation , and to regulate tissue growth is evolutionarily conserved from fly to men. "
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    Molecular Biology and Evolution 03/2014; 31(7). DOI:10.1093/molbev/msu115 · 9.11 Impact Factor
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