Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling.
The Hippo (Hpo) pathway is a central determinant of tissue size in both Drosophila and higher organisms. The core of the pathway is a kinase cascade composed of an upstream kinase Hpo (MST1/2 in mammals) and a downstream kinase Warts (Wts, Lats1/2 in mammals), as well as several scaffold proteins, Sav, dRASSF, and Mats. Activation of the core kinase cassette results in phosphorylation and inactivation of the progrowth transcriptional coactivator Yki, leading to increased apoptosis and reduced tissue growth. The mechanisms that prevent inappropriate Hpo activation remain unclear, and in particular, the identity of the phosphatase that antagonizes Hpo is unknown. Using combined proteomic and RNAi screening approaches, we identify the dSTRIPAK PP2A complex as a major regulator of Hpo signaling. dSTRIPAK depletion leads to increased Hpo activatory phosphorylation and repression of Yki target genes in vivo, suggesting this phosphatase complex prevents Hpo activation during development.
Ribeiro
Paulo S
PS
Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Josué
Filipe
F
Wepf
Alexander
A
Wehr
Michael C
MC
Rinner
Oliver
O
Kelly
Gavin
G
Tapon
Nicolas
N
Gstaiger
Matthias
M
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development / Q000648:ultrastructure; D023281:Genomics / Q000379:methods; D005838:Genotype; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D015203:Reproducibility of Results; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D011494:Protein Kinases; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C517506:RASSF protein, Drosophila; C503814:Yki protein, Drosophila; C529534:mts protein, Drosophila; C465504:sav protein, Drosophila; C093503:wts protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases