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Updated: Aug 30, 2025

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
07:16

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

Published on: September 13, 2018

20.0K

Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in

Yuan Gu1, Yu Wang2, Zhao Sha2

  • 1Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, the State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032 China.

Cell Reports
|August 31, 2022
PubMed

Insights

Transmembrane protein KIRREL1 regulates the Hippo pathway by activating LATS1/2 kinases. KIRREL1 acts as a tumor suppressor, offering a potential drug target for cancers dependent on YAP/TAZ activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The Hippo tumor-suppressor pathway is crucial in regulating organ size and is often dysregulated in human cancers.
  • Targeting the mammalian Hippo pathway is challenging due to the absence of well-defined cell-surface regulators.
  • YAP/TAZ oncoproteins are key downstream effectors of the Hippo pathway, driving tumorigenesis when dysregulated.

Purpose of the Study:

  • To identify and characterize a novel cell-surface regulator of the Hippo tumor-suppressor pathway.
  • To elucidate the mechanism by which this regulator interacts with and modulates Hippo pathway components.
  • To evaluate the therapeutic potential and prognostic significance of this regulator in human cancers.

Main Methods:

  • Investigated the interaction of transmembrane protein KIRREL1 with Hippo pathway components SAV1 and LATS1/2.
  • Assessed the effect of KIRREL1 on LATS1/2 activation by MST1/2 (Hippo kinases).
  • Analyzed the regulation of KIRREL1 expression by YAP/TAZ via TEAD1-4 transcription factors.
  • Correlated KIRREL1 expression with YAP/TAZ target gene expression in clinical tumor specimens.
  • Evaluated the tumor-suppressive role of KIRREL1 using a mouse intrahepatic cholangiocarcinoma model.

Main Results:

  • Transmembrane protein KIRREL1 interacts with SAV1 and LATS1/2, promoting LATS1/2 activation by MST1/2.
  • LATS1/2 activation by KIRREL1 leads to inhibition of YAP/TAZ oncoprotein activity.
  • YAP/TAZ directly induce KIRREL1 expression in a TEAD1-4-dependent manner, establishing a negative feedback loop.
  • KIRREL1 expression positively correlates with YAP/TAZ target gene expression and predicts poor prognosis in clinical tumors.
  • Transgenic expression of KIRREL1 suppressed tumorigenesis in a mouse model, confirming its tumor-suppressor role.

Conclusions:

  • KIRREL1 acts as a cell-surface regulator that forms a negative feedback loop within the Hippo pathway.
  • KIRREL1's interaction with SAV1 and LATS1/2 modulates Hippo pathway signaling, impacting YAP/TAZ activity.
  • KIRREL1 serves as a potential prognostic marker and therapeutic target for cancers exhibiting YAP/TAZ dependency.
Keywords:
CP: CancerCP: Cell biologyHippo pathwayKIRREL1LATS1MST1SAV1TAZYAPbiomarkercontact inhibitiontherapeutic target

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