PMID- 20798049
OWN - NLM
STAT- MEDLINE
DCOM- 20101007
LR  - 20211203
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 36
DP  - 2010 Sep 7
TI  - The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in 
      Drosophila.
PG  - 15810-5
LID - 10.1073/pnas.1004060107 [doi]
AB  - 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.
FAU - Chen, Chiao-Lin
AU  - Chen CL
AD  - Department of Biochemistry and Molecular Biology, University of Texas M. D. 
      Anderson Cancer Center, Houston, 77030, USA.
FAU - Gajewski, Kathleen M
AU  - Gajewski KM
FAU - Hamaratoglu, Fisun
AU  - Hamaratoglu F
FAU - Bossuyt, Wouter
AU  - Bossuyt W
FAU - Sansores-Garcia, Leticia
AU  - Sansores-Garcia L
FAU - Tao, Chunyao
AU  - Tao C
FAU - Halder, Georg
AU  - Halder G
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - CA16672/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100823
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Drosophila Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (crb protein, Drosophila)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (hpo protein, Drosophila)
SB  - IM
MH  - Animals
MH  - Cell Polarity/*physiology
MH  - Cell Proliferation
MH  - Drosophila
MH  - Drosophila Proteins/*metabolism/*physiology
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Membrane Proteins/*physiology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Signal Transduction/*physiology
PMC - PMC2936591
COIS- The authors declare no conflict of interest.
EDAT- 2010/08/28 06:00
MHDA- 2010/10/12 06:00
PMCR- 2011/03/07
CRDT- 2010/08/28 06:00
PHST- 2010/08/28 06:00 [entrez]
PHST- 2010/08/28 06:00 [pubmed]
PHST- 2010/10/12 06:00 [medline]
PHST- 2011/03/07 00:00 [pmc-release]
AID - 1004060107 [pii]
AID - 201004060 [pii]
AID - 10.1073/pnas.1004060107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15810-5. doi: 
      10.1073/pnas.1004060107. Epub 2010 Aug 23.