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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor
Published on: September 13, 2018
Homeodomain-interacting protein kinase regulates Yorkie activity to promote tissue growth
Joanna Chen1, Esther M Verheyen
1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Abstract:
The Hippo (Hpo) tumor suppressor pathway regulates tissue size by inhibiting cell proliferation and promoting apoptosis. The core components of the pathway, Hpo, Salvador, Warts (Wts), and Mats, form a kinase cascade to inhibit the activity of Yorkie (Yki), the transcriptional effector of the pathway. Homeodomain-interacting protein kinases (Hipks) are a family of conserved serine/threonine kinases that function as regulators of various transcription factors to regulate developmental processes including proliferation, differentiation, and apoptosis. Hipk can induce tissue overgrowth in Drosophila. We demonstrate that Hipk is required to promote Yki activity. Hipk affects neither Yki stability nor its subcellular localization. Moreover, hipk knockdown suppresses the overgrowth and target gene expression caused by hyperactive Yki. Hipk phosphorylates Yki and in vivo analyses show that Hipk's regulation of Yki is kinase-dependent. To our knowledge, this is the first kinase identified to positively regulate Yki.
Insights
Homeodomain-interacting protein kinases (Hipks) promote Yorkie (Yki) activity, a key component of the Hippo pathway. This study identifies Hipk as the first kinase that positively regulates Yki, impacting tissue growth.
Area of Science:
- Cell biology
- Molecular biology
- Developmental biology
Background:
- The Hippo pathway (Hpo) is a crucial regulator of tissue size, controlling cell proliferation and apoptosis.
- The core Hippo pathway kinase cascade inhibits the transcriptional effector Yorkie (Yki).
- Homeodomain-interacting protein kinases (Hipks) are serine/threonine kinases involved in regulating transcription factors and developmental processes.
Purpose of the Study:
- To investigate the role of Hipk in the Hippo tumor suppressor pathway.
- To determine if Hipk regulates the activity of the transcriptional effector Yorkie (Yki).
Main Methods:
- Investigated Hipk's effect on Yki stability and subcellular localization.
- Utilized knockdown experiments to assess Hipk's role in Yki-mediated overgrowth and gene expression.
- Performed in vivo analyses to examine Hipk's kinase-dependent regulation of Yki.
Main Results:
- Hipk is required for promoting Yki activity.
- Hipk does not affect Yki stability or its subcellular localization.
- Hipk knockdown suppresses overgrowth and target gene expression induced by hyperactive Yki.
- Hipk directly phosphorylates Yki in a kinase-dependent manner.
Conclusions:
- Hipk is a novel positive regulator of Yki activity within the Hippo pathway.
- This study identifies Hipk as the first kinase demonstrated to positively regulate Yki.
- Hipk's kinase activity is essential for its regulation of Yki and subsequent control of tissue growth.
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