Elucidating the mechanism of mechanotransduction through YAP and TAZ

Project Information

YAP MECHANO

Grant agreement ID: 798570

DOI

10.3030/798570

Project closed

EC signature date 26 March 2018

Start date 1 January 2019

End date 31 December 2020

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 168 277,20

EU contribution

€ 168 277,20

Coordinated by

UNIVERSITA DEGLI STUDI DI PADOVA
Italy

Periodic Reporting for period 1 - YAP MECHANO (Elucidating the mechanism of mechanotransduction through YAP and TAZ)

Reporting period: 2019-01-01 to 2020-12-31

Summary of the context and overall objectives of the project

Cells are at any moment exposed to mechanical cues, for the simple fact that they are embedded in tissues imposing defined geometrical and architectural constraints or, in vitro, cultured on 2D surfaces (or 3D matrices) dictating cell shape. The importance of these signals has long been appreciated but, until recently, how physical inputs affect gene expression and thus cell fate remained enigmatic. Understanding the molecular mechanisms that link mechanical cues to cell fate has important implications for our understanding of embryonic development, regeneration and adult tissue homeostasis. The corruption of this pathway in disease is thought to fuel tumour growth and progression as well as vascular remodelling in the context of arteriosclerosis. Uncovering the molecular players of the mechanotransduction pathway might allow us to develop new pharmacological strategies to interfere with disease development and progression.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In order to decipher the molecular mechanism of mechanotransduction, I employed a multi-pronged approach to tackle the problem from different perspectives. In the first part of the project we uncovered the kinetics of YAP/TAZ nuclear translocation upon actomyosin network tension. We next elucidated the role of nuclear mechanics or nuclear actin in YAP/TAZ nuclear localisation upon cytoskeletal strain. Next, we delineated the mechanotransduction pathway at a molecular level using crosslinking mass-spectrometry and biochemical validation. As a final step, I am now planning to assess the gain- and loss-of-function phenotype of these novel mechanotransduction pathway players in a range of systems to test their function and to establish the generality of my findings.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Uncovering the mechanotransduction pathway will not only greatly advance our understanding of cell biology, but also aid to identify potential targets for cancer therapy, as indeed the stiffening of the tumour environment is a driving factor in cancer progression.

YAP MECHANO in a nutshell