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Signalling through the Hippo (Hpo) pathway involves a kinase cascade, which leads to the phosphorylation and inactivation of the pro-growth transcriptional co-activator Yorkie (Yki). Despite the identification of a large number of pathway members and modulators, our understanding of the molecular events that lead to activation of Hpo and the downstream kinase Warts (Wts) remain incomplete. Recently, targeted degradation of several Hpo pathway components has been demonstrated as a means of regulating pathway activity. In particular, the stability of scaffold protein Salvador (Sav), which is believed to promote Hpo/Wts association, is crucially dependent on its binding partner Hpo. In a cell-based RNAi screen for ubiquitin regulators involved in Sav stability, we identify the HECT domain protein Herc4 (HECT and RLD domain containing E3 ligase) as a Sav E3 ligase. Herc4 expression promotes Sav ubiquitylation and degradation, while Herc4 depletion stabilises Sav. Interestingly, Hpo reduces Sav/Herc4 interaction in a kinase-dependent manner. This suggests the existence of a positive feedback loop, where Hpo stabilises its own positive regulator by antagonising Herc4-mediated degradation of Sav.

Original publication

DOI

10.1371/journal.pone.0131113

Type

Journal article

Journal

PLoS One

Publication Date

2015

Volume

10

Keywords

Amino Acid Sequence, Animals, Cell Cycle Proteins, Drosophila, Drosophila Proteins, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Protein Kinases, Protein-Serine-Threonine Kinases, RNA Interference, Sequence Alignment, Signal Transduction, Ubiquitin, Ubiquitin-Protein Ligases