RRC ID 47229
Author Jahanshahi M, Hsiao K, Jenny A, Pfleger CM.
Title The Hippo Pathway Targets Rae1 to Regulate Mitosis and Organ Size and to Feed Back to Regulate Upstream Components Merlin, Hippo, and Warts.
Journal PLoS Genet
Abstract Hippo signaling acts as a master regulatory pathway controlling growth, proliferation, and apoptosis and also ensures that variations in proliferation do not alter organ size. How the pathway coordinates restricting proliferation with organ size control remains a major unanswered question. Here we identify Rae1 as a highly-conserved target of the Hippo Pathway integrating proliferation and organ size. Genetic and biochemical studies in Drosophila cells and tissues and in mammalian cells indicate that Hippo signaling promotes Rae1 degradation downstream of Warts/Lats. In proliferating cells, Rae1 loss restricts cyclin B levels and organ size while Rae1 over-expression increases cyclin B levels and organ size, similar to Hippo Pathway over-activation or loss-of-function, respectively. Importantly, Rae1 regulation by the Hippo Pathway is crucial for its regulation of cyclin B and organ size; reducing Rae1 blocks cyclin B accumulation and suppresses overgrowth caused by Hippo Pathway loss. Surprisingly, in addition to suppressing overgrowth, reducing Rae1 also compromises survival of epithelial tissue overgrowing due to loss of Hippo signaling leading to a tissue "synthetic lethality" phenotype. Excitingly, Rae1 plays a highly conserved role to reduce the levels and activity of the Yki/YAP oncogene. Rae1 increases activation of the core kinases Hippo and Warts and plays a post-transcriptional role to increase the protein levels of the Merlin, Hippo, and Warts components of the pathway; therefore, in addition to Rae1 coordinating organ size regulation with proliferative control, we propose that Rae1 also acts in a feedback circuit to regulate pathway homeostasis.
Volume 12(8)
Pages e1006198
Published 2016-8-1
DOI 10.1371/journal.pgen.1006198
PII PGENETICS-D-16-00228
PMID 27494403
PMC PMC4975479
MeSH Animals Apoptosis / genetics Cell Proliferation / genetics Cyclin B / genetics Drosophila / genetics Drosophila / growth & development Drosophila Proteins / biosynthesis Drosophila Proteins / genetics* Gene Expression Regulation, Developmental Intracellular Signaling Peptides and Proteins / biosynthesis Intracellular Signaling Peptides and Proteins / genetics* Mitosis / genetics Neurofibromin 2 / biosynthesis Neurofibromin 2 / genetics* Nuclear Matrix-Associated Proteins / biosynthesis Nuclear Matrix-Associated Proteins / genetics* Nucleocytoplasmic Transport Proteins / biosynthesis Nucleocytoplasmic Transport Proteins / genetics* Organ Size Phenotype Protein Kinases / biosynthesis Protein Kinases / genetics* Protein-Serine-Threonine Kinases / biosynthesis Protein-Serine-Threonine Kinases / genetics* Signal Transduction Synthetic Lethal Mutations / genetics Wings, Animal / growth & development
IF 5.224
Times Cited 4
WOS Category GENETICS & HEREDITY
Resource
Drosophila 9862R-2 9862R-3