Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade
Copyright policy )Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade
In Drosophila and mammals, the canonical Hippo kinase cascade is mediated by Hpo/Mst acting through the intermediary kinase Wts/Lats to phosphorylate the transcriptional coactivator Yki/YAP/TAZ. Despite recent reports linking Yki/YAP/TAZ activity to the actin cytoskeleton, the underlying mechanisms are poorly understood and/or controversial. Using Drosophila imaginal discs as an in vivo model, we show that Wts, but not Hpo, is genetically indispensable for cytoskeleton-mediated subcellular localization of Yki. Through a systematic screen, we identify the Ste-20 kinase Happyhour (Hppy) and its mammalian counterpart MAP4K1/2/3/5 as an alternative kinase that phosphorylates the hydrophobic motif of Wts/Lats in a similar manner as Hpo/Mst. Consistent with their redundant function as activating kinases of Wts/Lats, combined loss of Hpo/Mst and Hppy/MAP4K abolishes cytoskeleton-mediated regulation of Yki/YAP subcellular localization, as well as YAP cytoplasmic translocation induced by contact inhibition. These Hpo/Mst-like kinases provide an expanded view of the Hippo kinase cascade in development and physiology.
- Johns Hopkins University School of Medicine United States
- Johns Hopkins Medicine United States
- Howard Hughes Medical Institute United States
Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, Fluorescent Antibody Technique, Cell Cycle Proteins, Protein Serine-Threonine Kinases, Real-Time Polymerase Chain Reaction, Cytoskeletal Proteins, Drosophila melanogaster, Imaginal Discs, Animals, Drosophila Proteins, RNA, Messenger, Phosphorylation, Cells, Cultured, Developmental Biology, Signal Transduction
Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, Fluorescent Antibody Technique, Cell Cycle Proteins, Protein Serine-Threonine Kinases, Real-Time Polymerase Chain Reaction, Cytoskeletal Proteins, Drosophila melanogaster, Imaginal Discs, Animals, Drosophila Proteins, RNA, Messenger, Phosphorylation, Cells, Cultured, Developmental Biology, Signal Transduction
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