Piezo1 balances focal and reticular adhesions to enable EGFR clathrin-mediated endocytosis

Cellular attachment to the extracellular matrix occurs via two types of adhesive structures: focal adhesions (FAs) and clathrin-enriched reticular adhesions (RAs). FAs facilitate cell migration and break down during cell division, while RAs hinder migration, remain throughout cell division, and assist in clathrin-mediated endocytosis (CME).

FAs increase in size with RhoA contractility, whereas RAs decrease in size. The precise mechanisms governing the balance between these two adhesion types are not yet understood. In this study, researchers discovered that Piezo1, a mechanically activated ion channel, serves as a primary regulator of the FA/RA balance. When Piezo1 detects mechanical stress, it triggers an influx of calcium ions, which activate Src family kinase Fyn.

Fyn then initiates two distinct actin polymerization pathways: one promoting FA and stress fiber growth through VAV2-RhoA, and another facilitating RA disassembly via N-WASP-Arp2/3. Reducing Piezo1 levels, either through inhibition or gene knockdown, results in smaller FAs and increased RA coverage. Notably, cells lacking Piezo1 struggle to internalize ligand-activated EGFR receptors on stiff surfaces, despite normal CME on softer surfaces.

This research underscores Piezo1's essential role in adapting EGFR CME to mechanical cues. Understanding this mechanosensor mechanism could lead to novel therapeutic strategies, particularly in the context of viral entry into host cells and cancer resistance to anti-EGFR antibody therapy.