title: Hippo pathway phylogenetics predicts monoubiquitylation of Salvador and Merlin/Nf2.
abstract: Recently we employed phylogenetics to predict that the cellular interpretation of TGF-β signals is modulated by monoubiquitylation cycles affecting the Smad4 signal transducer/tumor suppressor. This prediction was subsequently validated by experiments in flies, frogs and mammalian cells. Here we apply a phylogenetic approach to the Hippo pathway and predict that two of its signal transducers, Salvador and Merlin/Nf2 (also a tumor suppressor) are regulated by monoubiquitylation. This regulatory mechanism does not lead to protein degradation but instead serves as a highly efficient "off/on" switch when the protein is subsequently deubiquitylated. Overall, our study shows that the creative application of phylogenetics can predict new roles for pathway components and new mechanisms for regulating intercellular signaling pathways.
authors.affiliation: NextBio, Santa Clara, California, United States of America.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Wisotzkey
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Konikoff
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Newfeld
mesh_terms: D000818:Animals; D001499:Bayes Theorem; D018797:Cell Cycle Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016013:Likelihood Functions; D008239:Lysine / Q000737:chemistry; D025581:Neurofibromin 2 / Q000378:metabolism*; D010766:Phosphorylation; D010802:Phylogeny; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine; D025581:Neurofibromin 2; D017346:Protein Serine-Threonine Kinases; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C415864:SAV1 protein, human; C465504:sav protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases