Hippo Pathway

The Hippo pathway regulates organ size and suppresses tumorigenesis in multicellular organisms. Dysregulation of this pathway drives tumor formation in humans and mice. Central to this pathway is a kinase cascade consisting of Mst1/2 and Lats1/2 kinases and their activators Sav and Mob1. An important downstream effector of this pathway is the hybrid transcription factor complex YAP–TEAD.

We aim to understand the structural basis of Hippo pathway activation. As a promising start to this project, we have determined the structure of the YAP-binding domain of TEAD and studied the YAP–TEAD interaction. We have also solved the crystal structure of human Mst2 kinase in complex with its key regulator RASSF5. Recently, we have solved the crystal structures of the phospho-Mst2–Mob1 complex and the phospho-Mob1–Lats1 complex.

These studies have greatly advanced our understanding of the molecular mechanisms of the core Mst–Lats kinase activation in Hippo signaling. In the future, we will continue to use a combination of biophysical and biochemical approaches to carry out studies on Mst, Lats, and their regulators to establish the activation mechanisms of the Mst-Lats kinase cascade. This knowledge will ultimately aid the development of chemical compounds that activate the Hippo pathway, which can serve as leads for the development of new anti-cancer drugs.

RASSF5/Mst2 complex chart RASSF5/Mst2 complex