Arohan R. Subramanya, MD

Our laboratory studies a kinase signaling pathway that forms biomolecular condensates – membraneless droplet-like assemblies that form via a process called phase separation.
During cell shrinkage caused by hyperosmotic stress, water exits the cell, resulting in the crowding of cytoplasmic contents. In a recent paper (Boyd-Shiwarski et al, Cell 2022), we showed that WNK kinases sense this crowding, forming phase separated condensates that activate a phosphorylation-dependent cell volume recovery signal. While the ancient and ubiquitous version of this cascade regulates fluid volume in cells throughout the body, kidney tubules uniquely leverage the crowding-induced signal to control salt and water reabsorption, blood pressure, and potassium balance. Thus, WNK kinases provide one of the first clear examples of a signaling pathway that forms biomolecular condensates to control cell and whole animal physiology.

This discovery has opened several avenues of investigation that could be potential rotation projects. These include:

(1) determining the mechanism by which WNK kinases activate signaling within condensates to drive cell volume rescue,

(2) elucidating signatures within the kinase that function as crowding-induced phase separation drivers,

(3) identifying novel signaling partners that reside within WNK droplets,

(4) testing the relevance of phase separation in physiology using established mouse models of kidney-specific WNK condensate hyperactivation and dysfunction, and

(5) testing how recently identified small molecule inhibitors of the WNK signaling pathway influence its stress-induced phase behavior.