The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila.
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.
Chen
Chiao-Lin
CL
Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA.
Gajewski
Kathleen M
KM
Hamaratoglu
Fisun
F
Bossuyt
Wouter
W
Sansores-Garcia
Leticia
L
Tao
Chunyao
C
Halder
Georg
G
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
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
Int Rev Cytol. 2007;262:253-302
17631191
Development. 2006 Jul;133(13):2539-51
16735478
Dev Cell. 2005 Nov;9(5):687-98
16256743
Nature. 2001 Dec 6;414(6864):638-43
11740560
Nature. 2001 Dec 6;414(6864):634-8
11740559
J Cell Sci. 2009 Jul 15;122(Pt 14):2351-9
19531584
Dev Cell. 2010 Feb 16;18(2):300-8
20159599
Front Biosci (Landmark Ed). 2009 Jan 01;14:2149-69
19273190
J Cell Biol. 2002 Sep 2;158(5):941-51
12213838
Development. 2008 Sep;135(17):2827-38
18697904
Nat Cell Biol. 2006 Jan;8(1):27-36
16341207
Nat Cell Biol. 2003 Oct;5(10):914-20
14502294
Dev Cell. 2009 Mar;16(3):411-20
19289086
Cell. 1990 Jun 1;61(5):787-99
2344615
Nat Rev Cancer. 2007 Mar;7(3):182-91
17318211
Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10532-7
20498073
Curr Biol. 2006 Nov 7;16(21):2090-100
16996265
Cancer Res. 2008 Jun 1;68(11):4105-15
18519669
Curr Biol. 2006 Nov 7;16(21):2081-9
16996266
Nat Genet. 2006 Oct;38(10):1142-50
16980976
Biochim Biophys Acta. 2008 Mar;1778(3):614-30
18005931
Dev Cell. 2006 Sep;11(3):363-74
16950127
J Cell Biol. 2000 Nov 13;151(4):891-904
11076972
Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14897-902
18809931
Nature. 2002 Mar 14;416(6877):143-9
11850625
Genes Dev. 2007 Apr 15;21(8):886-97
17437995
Curr Biol. 2000 Jan 27;10(2):76-85
10662667
Annu Rev Genet. 2001;35:747-84
11700298
Genes Dev. 2010 May;24(9):862-74
20439427
Annu Rev Genet. 2006;40:335-61
16872256
Nature. 2002 Mar 14;416(6877):178-83
11850624
Oncogene. 2008 Nov 24;27(55):6888-907
19029932
Cell. 1995 Jul 14;82(1):67-76
7606787
EMBO Rep. 2006 Mar;7(3):297-302
16440003
Dev Cell. 2008 Mar;14(3):377-87
18258485
Dev Cell. 2010 Feb 16;18(2):309-16
20159600
J Cell Biol. 2004 Aug 16;166(4):549-57
15302858
Dev Cell. 2010 Feb 16;18(2):288-99
20159598
Dev Biol. 2010 Jan 15;337(2):274-83
19913529
Curr Biol. 2010 Apr 13;20(7):582-90
20362445
Development. 2010 Feb;137(4):641-50
20110329
Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20362-7
18077345
J Cell Sci. 2009 Jul 15;122(Pt 14):2360-70
19531586
Nat Cell Biol. 2005 Dec;7(12):1232-9
16258546
Curr Opin Cell Biol. 2009 Dec;21(6):837-43
19846288