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

Dysregulation of the Hippo tumor suppressor pathway and hyperactivation of YAP/TAZ are frequently observed in human cancers and represent promising therapeutic targets. However, strategies targeting the mammalian Hippo pathway are limited due to the lack of a well-established cell surface regulator. By combining protein interactome data and clinical data, we have identified transmembrane protein KIRREL1 as an upstream regulator of the Hippo pathway. KIRREL1 interacts with Hippo pathway components SAV1 and LATS1/2 via its intracellular C-terminal domain and promotes LATS1/2 activation by MST1/2 (Hippo kinases), in turn inhibiting YAP/TAZ activity and target gene expression. Conversely, YAP/TAZ directly induce the expression of KIRREL1 in a TEAD1-4–dependent manner. In mouse liver tumors driven by YAP activation, KIRREL1 protein is robustly induced. Moreover, KIRREL1 expression positively correlates with canonical YAP/TAZ target gene expression in clinical tumor specimens and predicts poor prognosis. Finally, transgenic expression of KIRREL1 effectively blocked tumorigenesis in a mouse intrahepatic cholangiocarcinoma model, suggesting an important role of KIRREL1 in inhibiting cancer development. Together, these findings indicate that 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.