Cell adhesion molecule KIRREL1 is a feedback regulator of Hippo signaling recruiting SAV1 to cell-cell contact sites

The Hippo/YAP pathway controls cell proliferation through sensing physical and spatial organization of cells. How cell-cell contact is sensed by Hippo signaling is poorly understood. Here, we identified the cell adhesion molecule KIRREL1 as an upstream positive regulator of the mammalian Hippo pathway. KIRREL1 physically interacts with SAV1 and recruits SAV1 to cell-cell contact sites. Consistent with the hypothesis that KIRREL1-mediated cell adhesion suppresses YAP activity, knockout of KIRREL1 increases YAP activity in neighboring cells. Analyzing pan-cancer CRISPR proliferation screen data reveals KIRREL1 as the top plasma membrane protein showing strong correlation with known Hippo regulators, highlighting a critical role of KIRREL1 in regulating Hippo signaling and cell proliferation. During liver regeneration in mice, KIRREL1 is upregulated, and its genetic ablation enhances hepatic YAP activity, hepatocyte reprogramming and biliary epithelial cell proliferation. Our data suggest that KIRREL1 functions as a feedback regulator of the mammalian Hippo pathway through sensing cell-cell interaction and recruiting SAV1 to cell-cell contact sites.


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All experiments were repeated at least three times and all attempts to replicate the experiments performed here were successful Sample allocation was random Data acquisition in this study analysis was conducted in a blinded manner. The investigators were blinded to group allocation during data collection to avoid conscious and unconscious bias.  Table. All primary antibodies used in this study are widely used and well validated in literature and by the manufacturer.

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All cell lines tested negative for mycoplasma contamination No commonly misidentified lines were used Mus musculus. 16-21 week old male C57Bl/6 mice were used for the experiments in this study.
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For ISH on human livers, formalin-fixed paraffin-embedded (FFPE) sections of anonymized human needle liver biopsy tissue were obtained from the University Hospital Basel with ethics committee approval. Samples from 4 patients (aged 41-86; 3 males, 1 female) with liver injury-associated ductular reaction were used and analyzed in this study.
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The Formalin-fixed paraffin-embedded (FFPE) sections from human patients were obtained without compensation and used in accordance to the informed consent and approved by the ethics committee of northwest and central Switzerland (EKNZ).