STRUCTURAL STUDIES OF CORE KINASE CASCADE OF HIPPO SIGNALLING PATHWAY

Abstract

Hippo pathway is activated by multiple inputs which are sensed by the Mst1/2-Lats1/2 kinase cascade, where a multi-component complex is formed to regulate the downstream transcriptional machinery. The activity of this phosphorylation-dependent signal transduction depends on the molecular interplay of the core components; Mst1/2, Lats1/2, Sav and Mob1. The first part of the thesis aims to understand the role of Sav in Lats1/2 activation by Mst1/2. Our structural and biochemical findings suggest that Sav enhances the recruitment Lats1/2 kinases to Mst1/2 and facilitates its activation. In the second part of the thesis, we identified a new small molecule (Hit2) targeting both Mst2 and Lats1 kinases. We performed chemical modifications on Hit2 which resulted in increased affinity and better IC50 values. Crystal structures of Mst2 and Lats1 in complex with the compound (ES4) were determined. These findings propose a novel strategy to target Hippo signalling for therapeutic applications in regenerative medicine.