Editors' ChoiceHippo Signaling

Complex Inhibition

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Science Signaling  31 Aug 2010:
Vol. 3, Issue 137, pp. ec266
DOI: 10.1126/scisignal.3137ec266

Tissue size in Drosophila and mammals is determined by the Hippo (Hpo) signaling pathway, the core of which consists of a series of kinases, including Hpo and Warts (Wts), and scaffold proteins, including Salvador (Sav), that regulate the phosphorylation state and activity of the transcriptional coactivator Yorkie (Yki). Several proteins act upstream of Hpo to regulate tissue size, but the mechanisms that lead to the phosphorylation and activation of Hpo are unclear. In the absence of Hpo signaling, Yki translocates to the nucleus, where it combines with the transcription factor Scalloped (Sd) to activate the expression of genes whose products prevent apoptosis and promote proliferation, which leads to an increase in tissue size. Phosphorylation of Yki by Wts, which is downstream of Hpo, prevents Yki from entering the nucleus. Noting that a phosphatase that might antagonize Hpo activity has not yet been identified, Ribeiro et al. used genomic and proteomic analyses to search for inhibitors of Hpo signaling in Drosophila. Mass spectrometry analysis identified the PP2A phosphatase complex dSTRIPAK (Drosophila Striatin-interacting phosphatase and kinase) as part of the Hpo interactome. Depletion of Mts, the catalytic subunit of the phosphatase complex, resulted in the increased abundance of phosphorylated Hpo and Yki and the decreased activity of Yki compared with that in control cells. Components of the dSTRIPAK complex coimmunoprecipitated with Hpo and with dRASSF, a scaffold protein that is known to inhibit Hpo activity by competing with Sav for binding to Hpo; dSTRIPAK was not associated with the Hpo-Sav complex. Genetic experiments showed that dSTRIPAK acted upstream of Wts and Yki. The association of Hpo with a component of dSTRIPAK was partly dependent on dRASSF, which suggests that dRASSF might also inhibit Hpo signaling by recruiting the phosphatase. Together, these data suggest that Hpo signaling in Drosophila is inhibited by a phosphatase complex. Whether such a mechanism also exists in mammalian Hpo signaling remains to be determined.

P. S. Ribeiro, F. Josué, A. Wepf, M. C. Wehr, O. Rinner, G. Kelly, N. Tapon, M. Gstaiger, Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling. Mol. Cell 39, 521–534 (2010). [PubMed]

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