Kindlin-2 Inhibits the Hippo Signaling Pathway by Promoting Degradation of MOB1

Abstract

Summary: The Hippo signaling pathway plays a key role in development and cancer progression. However, molecules that intrinsically inhibit this pathway are less well known. Here, we report that the focal adhesion molecule Kindlin-2 inhibits Hippo signaling by interacting with and degrading MOB1 and promoting the interaction between MOB1 and the E3 ligase praja2. Kindlin-2 thus inhibits the phosphorylation of LATS1 and YAP and promotes YAP translocation into the nucleus, where it activates downstream Hippo target gene transcription. Kindlin-2 depletion activates Hippo/YAP signaling and alleviates renal fibrosis in Kindlin-2 knockout mice with unilateral ureteral occlusion (UUO). Moreover, Kindlin-2 levels are negatively correlated with MOB1 and phosphorylated (p) YAP in samples from patients with renal fibrosis. Altogether, these results demonstrate that Kindlin-2 inhibits Hippo signaling through degradation of MOB1. A specific long-lasting siRNA against Kindlin-2 effectively alleviated UUO-induced renal fibrosis and could be a potential therapy for renal fibrosis. : Song et al. demonstrate that Kindlin-2 inhibits Hippo pathway by enhancing the interaction between MOB1 and E3 ligase praja2 and promoting MOB1 degradation. Kindlin-2 depletion activates the Hippo pathway and alleviates renal fibrosis in UUO mouse model. A specific long-lasting siRNA against Kindlin-2 is of therapeutic value for renal fibrosis. Keywords: Hippo signaling, Kindlin-2, MOB1, YAP, renal fibrosis, siRNA, unilateral ureteral occlusion, praja2