Developmental Biology

The Tao of the Hippo

Science Signaling  22 Nov 2011:
Vol. 4, Issue 200, pp. ec322
DOI: 10.1126/scisignal.4200ec322

The Hippo signaling pathway limits cell proliferation and restricts organ and tissue growth. Activation of the kinase Hippo (Hpo) stimulates the downstream kinase Warts (Wts) to phosphorylate Ser168 of the transcription factor Yorkie (Yki), thus inactivating it. Hpo is a Sterile 20-like family kinase, leading Boggiano et al. to investigate whether other kinases in this family participated in Hippo signal transduction. An RNA interference (RNAi) screen in Drosophila revealed that loss of Tao-1 led to larger than normal wing and eye imaginal discs. In addition, Tao-1 deficiency resulted in increased transcription of Hippo pathway target genes. Tao-1 phosphorylated Hpo at Thr195 (which activates Hpo), and genetic interaction and biochemistry assays revealed that overexpression of Tao-1 in the wing increased phosphorylation of Wts, the downstream target of Hpo and a measure of Hippo pathway activation. The cytoplasmic proteins Merlin (Mer) and Expanded (Ex) promote the activation of Hpo. Depletion of Mer or Ex did not decrease Tao-1–mediated phosphorylation of Wts, whereas depletion of Tao-1 prevented phosphorylation of Wts in cells overexpressing Mer and Ex, suggesting that Mer and Ex function upstream of Tao-1. To identify regulators of the Hippo pathway, Poon et al. performed an RNAi screen in a Drosophila yki transgenic line that expressed a constitutively active form of Yki, which results in larger eyes, a phenotype that was accentuated by knockdown of Tao-1. Furthermore, Tao-1 depletion in third-instar larval eye discs caused normally quiescent cells to become mitotic and increased the numbers of interommatidial cells, effects that are also seen with increased activation of Yki. As indicated by various Yki reporter genes, knockdown of Tao-1 in wing imaginal discs elicited increased Yki activity, which required the kinase activity of Tao-1 as well as its coiled-coil and central domains. Overexpression of wts and the Hippo pathway scaffold protein Salvador (Sav) causes a small eye phenotype, which was enhanced with overexpression of Tao-1, an effect that required the kinase activity of Tao-1. Overexpression of Tao-1 increased phosphorylation of Yki at Ser168, which required the presence of Hpo. The mammalian ortholog of Hpo is MST1/2, and TAO1 phosphorylated MST1/2 in vitro. Thus, these studies show that Tao-1 phosphorylates Hpo to promote activation of the Hippo pathway, a function that may be evolutionarily conserved.

J. C. Boggiano, P. J. Vanderzalm, R. G. Fehon, Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway. Dev. Cell 21, 888–895 (2011). [PubMed]

C. L. C. Poon, J. I. Lin, X. Zhang, K. F. Harvey, The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway. Dev. Cell 21, 896–906 (2011). [PubMed]