Periodic Reporting for period 1 - YAP MECHANO (Elucidating the mechanism of mechanotransduction through YAP and TAZ)
Periodo di rendicontazione: 2019-01-01 al 2020-12-31
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.
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.
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.