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Genes 2016, 7(8), 44; doi:10.3390/genes7080044

Unveiling Hidden Dynamics of Hippo Signalling: A Systems Analysis

1
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton Victoria 3800, Australia
2
Biomedicine Discovery Institute, Monash University, Clayton Victoria 3800, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Paul Reynolds
Received: 11 May 2016 / Revised: 27 July 2016 / Accepted: 29 July 2016 / Published: 5 August 2016
(This article belongs to the Special Issue Hippo Signaling Pathway)
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Abstract

The Hippo signalling pathway has recently emerged as an important regulator of cell apoptosis and proliferation with significant implications in human diseases. In mammals, the pathway contains the core kinases MST1/2, which phosphorylate and activate LATS1/2 kinases. The pro-apoptotic function of the MST/LATS signalling axis was previously linked to the Akt and ERK MAPK pathways, demonstrating that the Hippo pathway does not act alone but crosstalks with other signalling pathways to coordinate network dynamics and cellular outcomes. These crosstalks were characterised by a multitude of complex regulatory mechanisms involving competitive protein-protein interactions and phosphorylation mediated feedback loops. However, how these different mechanisms interplay in different cellular contexts to drive the context-specific network dynamics of Hippo-ERK signalling remains elusive. Using mathematical modelling and computational analysis, we uncovered that the Hippo-ERK network can generate highly diverse dynamical profiles that can be clustered into distinct dose-response patterns. For each pattern, we offered mechanistic explanation that defines when and how the observed phenomenon can arise. We demonstrated that Akt displays opposing, dose-dependent functions towards ERK, which are mediated by the balance between the Raf-1/MST2 protein interaction module and the LATS1 mediated feedback regulation. Moreover, Ras displays a multi-functional role and drives biphasic responses of both MST2 and ERK activities; which are critically governed by the competitive protein interaction between MST2 and Raf-1. Our study represents the first in-depth and systematic analysis of the Hippo-ERK network dynamics and provides a concrete foundation for future studies. View Full-Text
Keywords: hippo signaling; ERK MAPK signaling; mathematical modelling; systems analysis; network dynamics; cell fate determination; feedback regulation hippo signaling; ERK MAPK signaling; mathematical modelling; systems analysis; network dynamics; cell fate determination; feedback regulation
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Shin, S.-Y.; Nguyen, L.K. Unveiling Hidden Dynamics of Hippo Signalling: A Systems Analysis. Genes 2016, 7, 44.

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