EMBO Fellows Meeting 2012

Wouter Bossuyt
EMBO Fellows Meeting 2012
An evolutionary switch in the regulation of the Hippo pathway between mice and
flies
Abstract
The Hippo pathway plays a key role in controlling organ size in different species. However, while the core of
the Hippo pathway is highly conserved throughout the animal kingdom, many of the currently identified
upstream components in flies and mammals are different. Here we analyzed whether these apparent
differences are due to our limited understanding of the Hippo pathway in different organisms or whether the
upstream regulation of the Hippo pathway is indeed different between flies and mammals. We traced the
evolutionary history of pathway components and their functional domains, and coupled it with in vivo
structure-function analyses. We identified an evolutionary switch in the upstream inputs of the Hippo pathway
at the base of the arthropod lineage. In this evolutionary transition, the Fat cadherin, and the FERM domain
protein Expanded gained novel domains that connect them to the Hippo pathway, while the cell-adhesion
receptor Echinoid and the atypical myosin Dachs evolved to become novel components of the Hippo pathway.
Subsequently, the downstream Hippo effector Yap lost it’s PDZ-binding motif that interacts with proteins at the
cell junctions, such as Zo-1 and Zo-2 and Amot, a junctional adaptor protein which was also lost it’s Yap
interaction and was subsequently lost in higher arthropods. We conclude that fundamental differences exist in
the upstream regulatory mechanisms of Hippo signaling between flies and vertebrates.
Wouter Bossuyt, Chiao-Lin Chen, Marius Sudol, Artyom Kopp, Georg Halder,
14-17 June 2012, Heidelberg, Germany