title: Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded.
abstract: The Hippo pathway is emerging as a key evolutionarily conserved signaling mechanism that controls organ size. Three membrane-associated proteins, Kibra, Merlin, and Expanded, regulate pathway activity, but the precise molecular mechanism by which they function is still poorly understood. Here we provide evidence that Merlin and Kibra activate Hippo signaling in parallel to Expanded at a spatially distinct cellular domain, the medial apical cortex. Merlin and Kibra together recruit the adapter protein Salvador, which in turn recruits the core kinase Hippo. In addition, we show that Crumbs has a dual effect on Hippo signaling. Crumbs promotes the ability of Expanded to activate the pathway but also sequesters Kibra to downregulate Hippo signaling. Together, our findings elucidate the mechanism of Hippo pathway activation by Merlin and Kibra, identify a subcellular domain for Hippo pathway regulation, and demonstrate differential activity of upstream regulators in different subcellular domains.
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Su
authors.affiliation: Department of Ecology and Evolutionary Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Michael Z
authors.initials: MZ
authors.lastname: Ludwig
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA; Committee on Development, Regeneration and Stem Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jiajie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA; Committee on Development, Regeneration and Stem Cell Biology, The University of Chicago, Chicago, IL 60637, USA. Electronic address: rfehon@uchicago.edu.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Fehon
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D016764:Cell Polarity; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D060227:Imaginal Discs / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D025581:Neurofibromin 2; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014921:Wings, Animal / Q000166:cytology; D000099317:Hippo Kinases
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D025581:Neurofibromin 2; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C085090:ex protein, Drosophila; C548168:kibra protein, Drosophila; C099885:merlin, Drosophila; C465504:sav protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases
keywords: Crumbs; Expanded; Hippo; Hippo pathway; Kibra; Merlin; Salvador; Yorkie; apical medial domain; growth control