Regulation of Hippo signaling by mechanical stimuli.

 The ability to sense and respond to mechanical strain is critical for numerous cellular behaviors such as cell fate determination, tissue regeneration, and the ability to halt proliferation when cells reach an ideal density. The Hippo pathway controls cell-density-dependent inhibition of growth by measuring and responding to the mechanical strain experienced by the cell. Density-dependent-inhibition of growth is typically lost in cancers. How the Hippo pathway senses mechanical strain is poorly understood, but it is known that the pathway monitors mechanical strain both indirectly through its effects on the actin cytoskeleton and more directly by sensing tension at cell-cell junctions. My lab has used proteomics based approaches to identify candidate mechanosensors for the Hippo pathway. This work has led to potential sensors for F-actin levels and tension at cell-cell junctions. We identified the angiomotin proteins as Hippo pathway sensors for F-actin levels and have also uncovered new Hippo pathway regulators at cell-cell junctions that may directly sense tension across tissues (see below). We are currently developing proteomics approaches to determine if the mechanosensors we identified control additional cellular pathways in response to mechanical strain  

Relevant Publications:

Paramasivam M, Sarkeshik A, Yates JR, 3rd, Fernandes MJ, McCollum D. Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor. Mol Biol Cell. 2011;22(19):3725-33. Epub 2011/08/13. doi: mbc.E11-04-0300 [pii]10.1091/mbc.E11-04-0300. PubMed PMID: 21832154; PMCID: PMC3183025.

Dutta S, Mana-Capelli S, Paramasivam M, Dasgupta I, Cirka H, Billiar K, McCollum D. TRIP6 inhibits Hippo signaling in response to tension at adherens junctions. EMBO Rep. 2018;19(2):337-50. Epub 2017/12/10. doi: 10.15252/embr.201744777. PubMed PMID: 29222344; PMCID: PMC5797958.