Hippo pathway mechanical force signalling in T cells
The hippo pathway is an established regulator of proliferation and cell fate during development (Papaspyropoulos et al.), with loss of activity associated with nearly all solid cancers including pancreatic ductal adenocarcinoma. The pathway transduces cellular signals via the RASSF1-6 and Sav1 protein scaffolds to MST and LATS kinases, which we have identified to modify chromatin and transcription by YAP/TAZ (Pefani et al.; Pankova et al.). Mechanical force on the cytoskeleton is widely described to block the hippo pathway and promote YAP/TAZ nuclear localisation. We have recently demonstrated that RASSF1A and MST2 reside at the nuclear envelope to regulate nuclear actin levels (Chatzifrangkeskou et al.) and respond to mechanical force to regulate YAP (Pankova et al.). We have uncovered a novel pathway linking both events in response to nuclear envelope tension and we now want to explore this in physiological context. Intriguingly, single cell sequencing data from the www.proteinatlas.org identifies RASSF1A and MST2 as expressed in T cells (in particular g/d Tcells). Moreover, physical tension upon TCR engagement is a mechanical cue that regulates actin (Colin-York et al.) and nuclear actin filaments have been described as required for CD4-Tcell transcriptional responses (Tsopoulidis et al.).
Loss of RASSF1A by epigenetic silencing contributes to widespread tumour development. We find a frequent germline polymorphism in human fails to detect mechanical force and predisposes to tumours. This is recapitulated in a mouse model where the allele accelerates colorectal and pancreatic dysplasia, however we do not know whether this is due to poor immunoediting by Tcells. This project is a collaboration between Eric O’Neill (hippo pathway signalling pancreatic cancer and mechnotransduction) and Marco Fritzsche, Kennedy Institute for Rheumatology (Tcell mechanobiology) in which we will question how RASSF1A and MST kinases contribute to Tcell receptor signalling and actin mechanics. The ultimate aim is to determine whether this is an important component of tumour control.
- Papaspyropoulos et al. 2018
- Pefani et al. EMBO J 2018;
- Pankova et al. EMBO J 2019;
- Chatzifrangkeskou et al. EMBO J 2019;
- Colin-York et al. Cell Report 2019;
- Tsopoulidis et al. Sci. Immunol. 2019