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A novel partner of Scalloped regulates Hippo signaling via antagonizing Scalloped-Yorkie activity.

ABSTRACT: The Hippo (Hpo) pathway controls tissue growth and organ size by regulating the activity of transcriptional co-activator Yorkie (Yki), which associates with transcription factor Scalloped (Sd) in the nucleus to promote downstream target gene expression. Here we identify a novel protein Sd-Binding-Protein (SdBP)/Tgi, which directly competes with Yki for binding to Sd through its TDU domains and inhibits the Sd-Yki transcriptional activity. We also find that SdBP retains Yki in the nucleus through the association with Yki WW domains via its PPXY motifs. Collectively, we identify SdBP as a novel component of the Hpo pathway, negatively regulating the transcriptional activity of Sd-Yki to restrict tissue growth.

SUBMITTER: Guo T

PROVIDER: S-EPMC3790236 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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A novel partner of Scalloped regulates Hippo signaling via antagonizing Scalloped-Yorkie activity.

Guo Tong T Lu Yi Y Li Peixue P Yin Meng-Xin MX Lv Dekang D Zhang Wenjing W Wang Huizhen H Zhou Zhaocai Z Ji Hongbin H Zhao Yun Y Zhang Lei L

Cell research 20130903 10

The Hippo (Hpo) pathway controls tissue growth and organ size by regulating the activity of transcriptional co-activator Yorkie (Yki), which associates with transcription factor Scalloped (Sd) in the nucleus to promote downstream target gene expression. Here we identify a novel protein Sd-Binding-Protein (SdBP)/Tgi, which directly competes with Yki for binding to Sd through its TDU domains and inhibits the Sd-Yki transcriptional activity. We also find that SdBP retains Yki in the nucleus through ...[more]

PMID: 23999857

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The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression.

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Validating upstream regulators of Yorkie activity in Hippo signaling through scalloped-based genetic epistasis.

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Differential Regulation of Cyclin E by Yorkie-Scalloped Signaling in Organ Development.

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Project description:The Fat-Hippo signaling pathway plays an important role in the regulation of normal organ growth during development, and in pathological growth during cancer. Fat-Hippo signaling controls growth through a transcriptional co-activator protein, Yorkie. A Fat-Hippo pathway has been described in which Yorkie is repressed by phosphorylation, mediated directly by the kinase Warts and indirectly by upstream tumor suppressors that promote Warts kinase activity. We present here evidence for an alternate pathway in which Yorkie activity is repressed by direct physical association with three other pathway components: Expanded, Hippo, and Warts. Each of these Yorkie repressors contains one or more PPXY sequence motifs, and associates with Yorkie via binding of these PPXY motifs to WW domains of Yorkie. This direct binding inhibits Yorkie activity independently from effects on Yorkie phosphorylation, and does so both in vivo and in cultured cell assays. These results emphasize the importance of the relative levels of Yorkie and its upstream tumor suppressors to Yorkie regulation, and suggest a dual repression model, in which upstream tumor suppressors can regulate Yorkie activity both by promoting Yorkie phosphorylation and by direct binding.

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KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases.

Project description:The Hippo pathway controls tissue growth and tumorigenesis by inhibiting cell proliferation and promoting apoptosis. Recent genetic studies in Drosophila identified Kibra as a novel regulator of Hippo signaling. Human KIBRA has been associated with memory performance and cell migration. However, it is unclear whether or how KIBRA is connected to the Hippo pathway in mammalian cells. Here, we show that KIBRA associates with and activates Lats (large tumor suppressor) 1 and 2 kinases by stimulating their phosphorylation on the hydrophobic motif. KIBRA overexpression stimulates the phosphorylation of Yes-associated protein (YAP), the Hippo pathway effector. Conversely, depletion of KIBRA by RNA interference reduces YAP phosphorylation. Furthermore, KIBRA stabilizes Lats2 by inhibiting its ubiquitination. We also found that KIBRA mRNA is induced by YAP overexpression in both murine and human cells, suggesting the evolutionary conservation of KIBRA as a transcriptional target of the Hippo signaling pathway. Thus, our study revealed a new connection between KIBRA and mammalian Hippo signaling.

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