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

Atanu Paul, Stefano Annunziato, Bo Lu, Tianliang Sun, Olivera Evrova, Lara Planas-Paz, Vanessa Orsini, Luigi M. Terracciano, Olga Charlat, Zinger Yang Loureiro, Lei Ji, Raffaella Zamponi, Frederic Sigoillot, Hong Lei, Alicia Lindeman, Carsten Russ, John S. Reece-Hoyes, Thomas B. Nicholson, Jan S. Tchorz and Feng Cong ()
Additional contact information
Atanu Paul: Novartis Pharma AG
Stefano Annunziato: Novartis Pharma AG
Bo Lu: Novartis Pharma AG
Tianliang Sun: Novartis Pharma AG
Olivera Evrova: Novartis Pharma AG
Lara Planas-Paz: Novartis Pharma AG
Vanessa Orsini: Novartis Pharma AG
Luigi M. Terracciano: Humanitas University
Olga Charlat: Novartis Pharma AG
Zinger Yang Loureiro: Novartis Pharma AG
Lei Ji: Novartis Pharma AG
Raffaella Zamponi: Novartis Pharma AG
Frederic Sigoillot: Novartis Pharma AG
Hong Lei: Novartis Pharma AG
Alicia Lindeman: Novartis Pharma AG
Carsten Russ: Novartis Pharma AG
John S. Reece-Hoyes: Novartis Pharma AG
Thomas B. Nicholson: Novartis Pharma AG
Jan S. Tchorz: Novartis Pharma AG
Feng Cong: Novartis Pharma AG

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28567-3

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