title: The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila.
abstract: Defects in apical-basal cell polarity and abnormal expression of cell polarity determinants are often associated with cancer in vertebrates. In Drosophila, abnormal expression of apical-basal determinants can cause neoplastic phenotypes, including loss of cell polarity and overproliferation. However, the pathways through which apical-basal polarity determinants affect growth are poorly understood. Here, we investigated the mechanism by which the apical determinant Crumbs (Crb) affects growth in Drosophila imaginal discs. Overexpression of Crb causes severe overproliferation, and we found that loss of Crb similarly results in overgrowth of imaginal discs. Crb gain and loss of function caused defects in Hippo signaling, a key signaling pathway that controls tissue growth in Drosophila and mammals. Manipulation of Crb levels caused the up-regulation of Hippo target genes, genetically interacted with known Hippo pathway components, and required Yorkie, a transcriptional coactivator that acts downstream in the Hippo pathway, for target gene induction and overgrowth. Interestingly, Crb regulates growth and cell polarity through different motifs in its intracellular domain. A juxtamembrane FERM domain-binding motif is responsible for growth regulation and induction of Hippo target gene expression, whereas Crb uses a PDZ-binding motif to form a complex with other polarity factors. The Hippo pathway component Expanded, an apically localized adaptor protein, is mislocalized in both crb mutant cells and Crb overexpressing tissues, whereas the other Hippo pathway components, Fat and Merlin, are unaffected. Taken together, our data show that Crb regulates growth through Hippo signaling, and thus identify Crb as a previously undescribed upstream input into the Hippo pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA.
authors.forename: Chiao-Lin
authors.initials: CL
authors.lastname: Chen
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gajewski
authors.forename: Fisun
authors.initials: F
authors.lastname: Hamaratoglu
authors.forename: Wouter
authors.initials: W
authors.lastname: Bossuyt
authors.forename: Leticia
authors.initials: L
authors.lastname: Sansores-Garcia
authors.forename: Chunyao
authors.initials: C
authors.lastname: Tao
authors.forename: Georg
authors.initials: G
authors.lastname: Halder
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000502:physiology*; D049109:Cell Proliferation; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism* / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C064360:crb protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases
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