The tumor-suppressor gene fat controls tissue growth upstream of expanded in the hippo signaling pathway.
BACKGROUND
The tight control of cell proliferation and cell death is essential to normal tissue development, and the loss of this control is a hallmark of cancers. Cell growth and cell death are coordinately regulated during development by the Hippo signaling pathway. The Hippo pathway consists of the Ste20 family kinase Hippo, the WW adaptor protein Salvador, and the NDR kinase Warts. Loss of Hippo signaling in Drosophila leads to enhanced cell proliferation and decreased apoptosis, resulting in massive tissue overgrowth through increased expression of targets such as Cyclin E and Diap1. The cytoskeletal proteins Merlin and Expanded colocalize at apical junctions and function redundantly upstream of Hippo. It is not clear how they regulate growth or how they are localized to apical junctions.


RESULTS
We find that another Drosophila tumor-suppressor gene, the atypical cadherin fat, regulates both cell proliferation and cell death in developing imaginal discs. Loss of fat leads to increased Cyclin E and Diap1 expression, phenocopying loss of Hippo signaling. Ft can regulate Hippo phosphorylation, a measure of its activation, in tissue culture. Importantly, fat is needed for normal localization of Expanded at apical junctions in vivo. Genetic-epistasis experiments place fat with expanded in the Hippo pathway.


CONCLUSIONS
Together, these data suggest that Fat functions as a cell-surface receptor for the Expanded branch of the conserved Hippo growth control pathway.
Silva
Elizabeth
E
Samuel Lunenfeld Research Institute and Department of Medical Genetics and Microbiology, University of Toronto, Toronto M5G 1X5, Canada.
Tsatskis
Yonit
Y
Gardano
Laura
L
Tapon
Nic
N
McNeill
Helen
H
D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000235:genetics / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000502:physiology*; D049109:Cell Proliferation; D019927:Cyclin E / Q000378:metabolism; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology*; D005123:Eye / Q000196:embryology; D016147:Genes, Tumor Suppressor; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction; D000099317:Hippo Kinases
D015820:Cadherins; D015815:Cell Adhesion Molecules; D019927:Cyclin E; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C111891:DIAP1 protein, Drosophila; C085090:ex protein, Drosophila; C472307:ft protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases