Next Article in Journal
Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development
Next Article in Special Issue
Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy
Previous Article in Journal
Telomerase: The Devil Inside
Previous Article in Special Issue
Willing to Be Involved in Cancer
Article Menu

Export Article

Open AccessArticle
Genes 2016, 7(8), 44;

Unveiling Hidden Dynamics of Hippo Signalling: A Systems Analysis

Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton Victoria 3800, Australia
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)
Full-Text   |   PDF [2096 KB, uploaded 5 August 2016]   |  


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

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material


Share & Cite This Article

MDPI and ACS Style

Shin, S.-Y.; Nguyen, L.K. Unveiling Hidden Dynamics of Hippo Signalling: A Systems Analysis. Genes 2016, 7, 44.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Genes EISSN 2073-4425 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top