title: AJUBA LIM Proteins Limit Hippo Activity in Proliferating Cells by Sequestering the Hippo Core Kinase Complex in the Cytosol.
abstract: The Hippo pathway controls organ growth and is implicated in cancer development. Whether and how Hippo pathway activity is limited to sustain or initiate cell growth when needed is not understood. The members of the AJUBA family of LIM proteins are negative regulators of the Hippo pathway. In mammalian epithelial cells, we found that AJUBA LIM proteins limit Hippo regulation of YAP, in proliferating cells only, by sequestering a cytosolic Hippo kinase complex in which LATS kinase is inhibited. At the plasma membranes of growth-arrested cells, AJUBA LIM proteins do not inhibit or associate with the Hippo kinase complex. The ability of AJUBA LIM proteins to inhibit YAP regulation by Hippo and to associate with the kinase complex directly correlate with their capacity to limit Hippo signaling during Drosophila wing development. AJUBA LIM proteins did not influence YAP activity in response to cell-extrinsic or cell-intrinsic mechanical signals. Thus, AJUBA LIM proteins limit Hippo pathway activity in contexts where cell proliferation is needed.
authors.affiliation: The ICCE Institute, Washington University, St. Louis, Missouri, USA Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Jagannathan
authors.affiliation: The ICCE Institute, Washington University, St. Louis, Missouri, USA Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA.
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Schimizzi
authors.affiliation: The ICCE Institute, Washington University, St. Louis, Missouri, USA Department of Medicine (Oncology), Washington University, St. Louis, Missouri, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: The ICCE Institute, Washington University, St. Louis, Missouri, USA Department of Biochemistry and Biophysics, Washington University, St. Louis, Missouri, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Loza
authors.affiliation: Department of Molecular Genetics, Research Institute for Microbial Disease, Osaka University, Osaka, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Yabuta
authors.affiliation: Department of Molecular Genetics, Research Institute for Microbial Disease, Osaka University, Osaka, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nojima
authors.affiliation: The ICCE Institute, Washington University, St. Louis, Missouri, USA Department of Medicine (Oncology), Washington University, St. Louis, Missouri, USA Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri, USA glongmor@dom.wustl.edu.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Longmore
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D003600:Cytosol / Q000201:enzymology*; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D060588:LIM Domain Proteins / Q000378:metabolism*; D061986:MCF-7 Cells; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D014921:Wings, Animal / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases