Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in YAP/TAZ-active cancers

Yuan Gu; Yu Wang; Zhao Sha; Chenxi He; Yuwen Zhu; Jian Li; Aijuan Yu; Zhenxing Zhong; Xuefei Wang; Yihong Sun; Fei Lan; Fa-Xing Yu

doi:10.1016/j.celrep.2022.111296

Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in YAP/TAZ-active cancers

Cell Rep. 2022 Aug 30;40(9):111296. doi: 10.1016/j.celrep.2022.111296.

Authors

Yuan Gu¹, Yu Wang², Zhao Sha², Chenxi He³, Yuwen Zhu², Jian Li², Aijuan Yu², Zhenxing Zhong², Xuefei Wang⁴, Yihong Sun⁴, Fei Lan³, Fa-Xing Yu⁵

Affiliations

¹ Institute 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.
² Institute 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.
³ Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
⁴ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032 China.
⁵ Institute 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. Electronic address: fxyu@fudan.edu.cn.

PMID: 36044856
DOI: 10.1016/j.celrep.2022.111296

Abstract

The Hippo tumor-suppressor pathway is frequently dysregulated in human cancers and represents a therapeutic target. However, strategies targeting the mammalian Hippo pathway are limited because of the lack of a well-established cell-surface regulator. Here, we show that transmembrane protein KIRREL1, by interacting with both SAV1 and LATS1/2, promotes LATS1/2 activation by MST1/2 (Hippo kinases), and LATS1/2 activation, in turn, inhibits activity of YAP/TAZ oncoproteins. Conversely, YAP/TAZ directly induce the expression of KIRREL1 in a TEAD1-4-dependent manner. Indeed, KIRREL1 expression positively correlates with canonical YAP/TAZ target gene expression in clinical tumor specimens and predicts poor prognosis. Moreover, transgenic expression of KIRREL1 effectively blocks tumorigenesis in a mouse intrahepatic cholangiocarcinoma model, indicating a tumor-suppressor role of KIRREL1. Hence, KIRREL1 constitutes a negative feedback mechanism regulating the Hippo pathway and serves as a cell-surface marker and potential drug target in cancers with YAP/TAZ dependency.

Keywords: CP: Cancer; CP: Cell biology; Hippo pathway; KIRREL1; LATS1; MST1; SAV1; TAZ; YAP; biomarker; contact inhibition; therapeutic target.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing* / metabolism
Animals
Carcinogenesis* / genetics
Carcinogenesis* / metabolism
Cell Cycle Proteins* / metabolism
Cholangiocarcinoma / metabolism
Feedback
Hippo Signaling Pathway*
Humans
Mammals / metabolism
Membrane Proteins* / metabolism
Mice
Phosphoproteins / metabolism
Protein Serine-Threonine Kinases
Transcription Factors / metabolism
Transcriptional Coactivator with PDZ-Binding Motif Proteins / metabolism
Tumor Suppressor Proteins / metabolism
YAP-Signaling Proteins / metabolism

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
KIRREL1 protein, human
Kirrel1 protein, mouse
Membrane Proteins
Phosphoproteins
Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Tumor Suppressor Proteins
YAP-Signaling Proteins
Protein Serine-Threonine Kinases