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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    • "Models of spatial regulation of LATS1/2 kinase activities were proposed a long time ago and have been further refined in the last few years. Early studies have shown that Hpo/Sav interact with Mer/Ex and that Wts associates with Kibra (Genevet et al. 2010; Yu et al. 2010). This interaction suggests that the Mer/Ex/Kibra complex may recruit Hpo and Wts to the apical plasma membrane and results in Wts phosphorylation by Hpo. "
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    ABSTRACT: The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell– cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.
    Full-text · Article · Jan 2016 · Genes & Development
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    • "The effect of Kibra varies in different tissue types. Loss of Kibra leads to accumulation of aPKC in the Drosophila posterior follicle cells[12]. After confirming that aPKC binds to Kibra in vitro, we examined the genetic interaction between Kibra and aPKC in regulating autophagy in the larval fat body. "
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    ABSTRACT: Autophagy is a bulk degradation system that functions in response to cellular stresses such as metabolic stress, endoplasmic reticulum stress, oxidative stress, and developmental processes. During autophagy, cytoplasmic components are captured in double-membrane vesicles called autophagosomes. The autophagosome fuses with the lysosome, producing a vacuole known as an autolysosome. The cellular components are degraded by lysosomal proteases and recycled. Autophagy is important for maintaining cellular homeostasis, and the process is evolutionarily conserved. Kibra is an upstream regulator of the hippo signaling pathway, which controls organ size by affecting cell growth, proliferation, and apoptosis. Kibra is mainly localized in the apical membrane domain of epithelial cells and acts as a scaffold protein. We found that Kibra is required for autophagy to function properly. The absence of Kibra caused defects in the formation of autophagic vesicles and autophagic degradation. We also found that the well-known cell polarity protein aPKC interacts with Kibra, and its activity affects autophagy upstream of Kibra. Constitutively active aPKC decreased autophagic vesicle formation and autophagic degradation. We confirmed the interaction between aPKC and Kibra in S2 cells and Drosophila larva. Taken together, our data suggest that Kibra and aPKC are essential for regulating starvation-induced autophagy.
    Full-text · Article · Nov 2015 · Biochemical and Biophysical Research Communications
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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.
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