Editors' ChoiceDevelopmental Biology

Hipk Antagonizes Hippo

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Science Signaling  18 Sep 2012:
Vol. 5, Issue 242, pp. ec245
DOI: 10.1126/scisignal.2003613

Signaling through the Hippo-Salvador-Warts (Wts) kinase cascade inhibits cell proliferation and promotes apoptosis by preventing nuclear accumulation of the transcriptional coactivator Yorkie (Yki in the fruit fly) or Yap (in vertebrates). Hippo-dependent phosphorylation of Yki by Wts prevents nuclear accumulation of Yki. In the nucleus, Yki cooperates with its partner Scalloped to promote expression of several target genes that inhibit apoptosis and promote mitosis. Two studies report that the serine-threonine kinase homeodomain-interacting protein kinase (Hipk) promotes Yki activity. Studies by Chen and Verheyen and by Poon et al. both demonstrate that, like overexpresison of yki or knockdown of wts, overexpresison of hipk in fly imaginal discs caused excessive cell proliferation, leading to tissue overgrowth, and stimulation of endogenous Yki transcriptional targets and reporter constructs. Reducing Hipk activity by mutation or RNA interference (RNAi) reduced both tissue size and expression of Yki targets. Hipk was required for maximal, but not all, Yki transcriptional regulatory activity. RNAi-mediated knockdown or mutation of hipk reversed the tissue overgrowth and target gene expression phenotypes induced by knockdown or mutation of wts, indicating that Hipk acted downstream or independently of Wts. Chen and Verheyen demonstrated that Hipk and Yki were present in the same protein complex, that Hipk phosphorylated Yki in vitro, and that Hipk’s kinase activity was required for its ability to induce tissue overgrowth and Yki reporter gene expression in wing discs. Poon et al. extended their analysis to a human Hipk homolog, HIPK2, showing that the kinase activity of HIPK2 was required for transcription of a YAP-activated luciferase reporter in 293T cells. The two studies come to many of the same conclusions; however, they differ on whether Hipk affects the subcellular localization of Yki. Chen and Verheyen saw no difference in the subcellular localization of endogenous Yki or an overexpressed fluorescent Yki fusion protein in wing clones overexpressing hipk. In contrast, Poon et al. noted that Yki was mostly cytoplasmic in disc tissues overexpressing yki alone but detected Yki in both the cytoplasm and nucleus when yki and hipk were overexpressed simultaneously. More work will be needed to address the question of Hipk’s effect on Yki’s subcellular localization. Wts-mediated phosphorylation of Yki in response to Hippo signaling promotes cytoplasmic retention of Yki by promoting its association with the 14-3-3 protein, but how this newly identified Hipk-mediated phosphorylation event controls Yki activity remains to be determined, as well as whether or how this activity of Hipk is regulated.

J. Chen, E. M. Verheyen, Homeodomain-interacting protein kinase regulates Yorkie activity to promote tissue growth. Curr. Biol. 22, 1582–1586 (2012). [PubMed]

C. L. C. Poon, X. Zhang, J. I. Lin, S. A. Manning, K. F. Harvey, Homeodomain-interacting protein kinase regulates Hippo pathway-dependent tissue growth. Curr. Biol. 22, 1587–1594 (2012). [PubMed]

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