Formation of clathrin-coated structures (CCSs) leads to mechanical perturbations in the cell membrane. Conversely, high membrane tension can also feed back to the endocytic process, causing it to stall, in a process termed ‘frustration’. Although CCS frustration has been linked to mechanically induced processes, such as cell proliferation, its role in signalling is still poorly understood. Now, Francesco Baschieri, Guillaume Montagnac and colleagues (Baschieri et al., 2020) show that cell compression can cause CCS frustration and activation of the ERK pathway. Compressing HeLa cells under an agarose plug reduces the dynamics of CCS components, resulting in an integrin-independent increase in the lifetime and frustration of CCSs. The authors demonstrate that ERK activation in compressed cells occurs due to the activity of the epidermal growth factor receptor (EGFR) kinase; chemical inhibition of this enzyme or knockdown of CCS components inhibits ERK activation. Moreover, EGFR recruitment to the CCSs depends on a disintegrin and metalloproteinase (ADAM) metalloproteases and paracrine shedding of heparin-binding EGF (HB-EGF). Finally, compression also promotes the recruitment of other receptor tyrosine kinases in a ligand-dependent manner, leading to ERK activation even when EGFR kinase activity is impaired. Thus, this study sheds light on the role of CCS frustration in the regulation of force-induced cellular responses.

• © 2020. Published by The Company of Biologists Ltd