Dr. Yvonne Schmitz

Nucleo-cytoplasmic antagonist shuttling

"I am interested in Wnt signalling and its role in differentiation, where I am focussing on the role of nucleo-cytoplasmic antagonist shuttling."

The Wnt signalling pathway plays a significant role in the differentiation of neuronal stem cells. The protein β-catenin is the main protagonist and transcriptional co-factor of the pathway. However, not only β-catenin, also its antagonists have been proven to shuttle between cytoplasm and nucleus, while the functional relevance of this is still controversial.
How is the output of the pathway influenced by antagonist shuttling? Can Wnt signalling benefit from antagonist shuttling?
We formulated different hypotheses in order to examine the relevance of nucleo-cytoplasmic antagonist shuttling using mathematical modelling. We have investigated different shuttling mechanism (diffusive and facilitated transport) and considered retention of β-catenin by the antagonists as a possible function.
We found that Wnt signalling can benefit from nucleo-cytoplasmic shuttling of β-catenin antagonists. The analysis of the models shows that the breakdown of β-catenin cytoplasmic retention induced by APC shuttling can maximize the output of the pathway. Our study indicates that one protein may have two opposing functions within the same pathway depending on the cellular context. Furthermore, we showed that saturated protein translocation can under certain conditions be modelled by pure diffusion. A difference in the shuttling rate constants of sufficient orders of magnitude leads to an accumulation in either compartment, which corresponds to saturation in translocation.