The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size.
BACKGROUND
The Hippo tumor-suppressor pathway has emerged as a key signaling pathway that controls tissue size in Drosophila. Merlin, the Drosophila homolog of the human Neurofibromatosis type-2 (NF2) tumor-suppressor gene, and the related protein Expanded are the most upstream components of the Hippo pathway identified so far. However, components acting upstream of Expanded and Merlin, such as transmembrane receptors, have not yet been identified.


RESULTS
Here, we report that the protocadherin Fat acts as an upstream component in the Hippo pathway. Fat is a known tumor-suppressor gene in Drosophila, and fat mutants have severely overgrown imaginal discs. We found that the overgrowth phenotypes of fat mutants are similar to those of mutants in Hippo pathway components: fat mutant cells continued to proliferate after wild-type cells stopped proliferating, and fat mutant cells deregulated Hippo target genes such as cyclin E and diap1. Fat acts genetically and biochemically upstream of other Hippo pathway components such as Expanded, the Hippo and Warts kinases, and the transcriptional coactivator Yorkie. Fat is required for the stability of Expanded and its localization to the plasma membrane. In contrast, Fat is not required for Merlin localization, and Fat and Merlin act in parallel in growth regulation.


CONCLUSIONS
Taken together, our data identify a cell-surface molecule that may act as a receptor of the Hippo signaling pathway.
Willecke
Maria
M
Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Hamaratoglu
Fisun
F
Kango-Singh
Madhuri
M
Udan
Ryan
R
Chen
Chiao-Lin
CL
Tao
Chunyao
C
Zhang
Xinwei
X
Halder
Georg
G
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005123:Eye / Q000196:embryology / Q000648:ultrastructure; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D025581:Neurofibromin 2 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014921:Wings, Animal / Q000033:anatomy & histology; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
D015820:Cadherins; D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D025581:Neurofibromin 2; D009687:Nuclear Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C085090:ex protein, Drosophila; C472307:ft protein, Drosophila; C099885:merlin, Drosophila; C093503:wts protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases