KSR1 is a scaffold for the Hippo signaling pathway.

The evolutionarily conserved Hippo signaling pathway regulates organ size and tissue homeostasis. Yes-associated protein (YAP) functions as a transcriptional co-activator and is a critical downstream effector of the Hippo signaling pathway. Altered crosstalk with oncogenic signaling pathways contributes to YAP dysregulation in cancer. Kinase Suppressor of Ras 1 (KSR1) scaffolds the Ras cascade. Some of the functions of the Ras and Hippo pathways in regulating cellular processes are similar. Nevertheless, the potential intersection of Ras and Hippo signaling has not been explored. Here, we identify KSR1 as a previously unrecognized scaffold of the Hippo pathway. We demonstrate that KSR1 constitutively binds to YAP and MST1 and forms a complex with LATS1. Moreover, KSR1 modulates YAP protein levels and its transcriptional activity, at least in part through the RhoA/actin axis. Our findings provide insight into the role of KSR1 as a scaffold of the Hippo signaling that could yield novel therapeutics.