Affiliation:
1. Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
Abstract
Liquid droplet has emerged as a flexible intracellular compartment that modulates various cellular processes. Here, we uncover an antimetastatic mechanism governed by the liquid droplets formed through liquid–liquid phase separation (LLPS) of SQSTM1/p62 and neighbor of BRCA1 gene 1 (NBR1). Some of the tyrosine kinase inhibitors (TKIs) initiated lysosomal stress response that promotes the LLPS of p62 and NBR1, resulting in the spreading of p62/NBR1 liquid droplets. Interestingly, in the p62/NBR1 liquid droplet, degradation of RAS-related C3 botulinum toxin substrate 1 was accelerated by cellular inhibitor of apoptosis protein 1, which limits cancer cell motility. Moreover, the antimetastatic activity of the TKIs was completely overridden in p62/NBR1 double knockout cells both in vitro and in vivo. Thus, our results demonstrate a function of the p62/NBR1 liquid droplet as a critical determinant of cancer cell behavior, which may provide insight into both the clinical and biological significance of LLPS.
Funder
MEXT | Japan Society for the Promotion of Science
Publisher
Proceedings of the National Academy of Sciences
Cited by
1 articles.
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