The complexity of biological control systems: An autophagy case study.


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Authors
Pavel, Mariana 
Tanasa, Radu 
Park, So Jung 
Rubinsztein, David C  ORCID logo  https://orcid.org/0000-0001-5002-5263
Abstract

Autophagy and YAP1-WWTR1/TAZ signalling are tightly linked in a complex control system of forward and feedback pathways which determine different cellular outcomes in differing cell types at different time-points after perturbations. Here we extend our previous experimental and modelling approaches to consider two possibilities. First, we have performed additional mathematical modelling to explore how the autophagy-YAP1 crosstalk may be controlled by posttranslational modifications of components of the pathways. Second, since analogous contrasting results have also been reported for autophagy as a regulator of other transduction pathways engaged in tumorigenesis (Wnt/β-catenin, TGF-β/Smads, NF-kB or XIAP/cIAPs), we have considered if such discrepancies may be explicable through situations involving competing pathways and feedback loops in different cell types, analogous to the autophagy-YAP/TAZ situation. Since distinct posttranslational modifications dominate those pathways in distinct cells, these need to be understood to enable appropriate cell type-specific therapeutic strategies for cancers and other diseases.

Description

Funder: UK Dementia Research Institute; Id: http://dx.doi.org/10.13039/501100017510

Keywords
YAP1 signalling, autophagy, cell heterogeneity, mathematical model, precision medicine, transduction pathways, Autophagy, Signal Transduction, Transforming Growth Factor beta
Journal Title
Bioessays
Conference Name
Journal ISSN
0265-9247
1521-1878
Volume Title
44
Publisher
Wiley
Sponsorship
Romanian Ministry of Research, Innovation and Digitization, CNCS/CCCDI‐UEFISCDI (PN‐III‐P1‐1.1‐PD‐2019‐0733)
PNCDI‐III (POC/448/1/1/127606)
We are grateful for funding from the UK Dementia Research Institute (funded by MRC, Alzheimer’s Research UK and the Alzheimer’s Society), a grant of the Romanian Ministry of Research, Innovation and Digitization, CNCS/CCCDI-UEFISCDI, project number PN-III-P1-1.1-PD-2019-0733, within PNCDI-III, and POC/448/1/1/127606 CENEMED project (M.P.).