A new study published in Cell Reports titled, “Kinase condensates enrich ATP and trigger autophosphorylation,” suggests that cellular phase separation, a mechanism that organizes biomolecules into dense, liquid-like condensates, may play a previously underappreciated role in regulating kinase activity. The findings suggest that aberrant condensate formation could contribute to oncogenic signaling while also offering new opportunities for drug targeting. 

“Many biological molecules have this propensity to spontaneously separate,” said Lindsay Case, PhD, assistant professor of biology at Massachusetts Institute of Technology (MIT) and corresponding author of the study. “We were really interested in asking, if we have these kinases forming droplets, what is the consequence of that in the context of signaling?” 

Phase separation occurs when proteins condense into highly concentrated liquid-like droplets within cells, analogous to oil droplets separating from vinegar. Although biomolecular condensates have emerged as important organizers of cellular processes, their impact on kinase signaling has remained incompletely understood. 

The researchers examined three kinases: focal adhesion kinase (FAK), Mst2, and Abl. Across all three systems, condensate formation increased kinase activity by concentrating enzymes and substrates, thereby promoting phosphorylation reactions. 

For FAK, the team found that elevated protein levels were sufficient to drive droplet formation and activate downstream growth signaling. The findings raise the possibility that FAK overexpression in tumors could promote constitutive signaling through condensate formation, potentially contributing to cancer progression and metastasis. 

“It was surprising that just by condensing this protein into a droplet, you can actually turn on a signaling pathway that should be turned off,” said Case. “If FAK concentration is too high, you’re always getting these droplets and you’re always signaling, regardless of what the receptors that are supposed to be controlling this are doing.” 

Mst2 and Abl also phase separated at high concentrations, which led to increased activity. For Mst2, phase separation is a strategy that healthy cells use to control the Hippo signaling pathway, which promotes cell growth and survival. Phase separation can also lead both enzymes to phosphorylate additional targets, and activate different signaling pathways. 

“It’s not just that you’re getting faster phosphorylation, but in those cases, the patterns of what is actually getting phosphorylated were very different inside of the droplet compared to what might be happening in a non-droplet context,” Case says. “The kinase is able to phosphorylate amino acid residues beyond the set of canonical sites that have been described before.” 

Mechanistically, the team found that kinase condensates selectively concentrate ATP, the phosphate donor required for kinase activity. Positively charged regions within kinases appear to recruit negatively charged ATP molecules to support phosphorylation. 

Using machine-learning analysis, the investigators predicted that approximately 45% of the roughly 500 human kinases possess the molecular features needed to form similar condensates. The findings suggest that phase separation may represent a widespread regulatory mechanism that could influence both normal cellular signaling and disease-associated kinase activity. 

In future work, Case hopes to explore designing drugs that could mimic ATP’s ability to be attracted into droplets within a cell, which could reduce side effects.

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