Editors' ChoiceCell Biology

Inhibiting Hippo

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Science Signaling  08 Jan 2013:
Vol. 6, Issue 257, pp. ec6
DOI: 10.1126/scisignal.2003940

Organ size during development is regulated by the Hippo (Hpo) signaling pathway. When activated, Hippo phosphorylates and activates the kinase Warts (Wts), which in turn phosphorylates the transcriptional coactivator Yorkie (Yki), which binds to 14-3-3 proteins and is retained in the cytosol. In the absence of Hpo signaling, unphosphorylated Yki translocates to the nucleus, where it stimulates the expression of genes involved in cell growth. Noting that the activities of Hpo and Wts are facilitated by their interaction with the scaffold proteins Salvador (Sav) and Mats, Wehr et al. searched for other regulators of Hpo signaling. They combined a protein-protein interaction detection method with an RNA interference (RNAi)–based screen in a Drosophila cell line and identified the gene CG42856, which encodes the Drosophila ortholog of salt-inducible kinase 3 (Sik3), as a negative regulator of Hpo signaling. The SIK proteins are members of the adenosine monophosphate (AMP)–activated protein kinase (AMPK) proteins, which are sensors of cellular energy. Knockdown of Sik2 or Sik3 in Drosophila cells increased the extent of Yki phosphorylation and decreased the expression of Yki target genes. In transgenic flies, expression of active Sik2 induced wing growth, whereas depletion of the Sik proteins had the opposite effect. Coimmunoprecipitation experiments and Western blot analyses showed that Sik2 and Sik3 bound to and phosphorylated the scaffold protein Sav. Phosphorylation of Sav disrupted its interaction with Hpo and Wts, resulting in decreased phosphorylation of Yki. Together, these data suggest that SIK proteins inhibit Hpo signaling in Drosophila, implicating Sik2 and Sik3 in growth control during development.

M. C. Wehr, M. V. Holder, I. Gailite, R. E. Saunders, T. M. Maile, E. Ciirdaeva, R. Instrell, M. Jiang, M. Howell, M. J. Rossner, N. Tapon, Salt-inducible kinases regulate growth through the Hippo signalling pathway in Drosophila. Nat. Cell Biol. 15, 61–71 (2013). [PubMed]

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