Force- and cell state–dependent recruitment of Piezo1 drives focal adhesion dynamics and calcium entry

Abstract

Mechanosensing is an integral part of many physiological processes including stem cell differentiation, fibrosis, and cancer progression. Two major mechanosensing systems—focal adhesions and mechanosensitive ion channels—can convert mechanical features of the microenvironment into biochemical signals. We report here unexpectedly that the mechanosensitive calcium-permeable channel Piezo1, previously perceived to be diffusive on plasma membranes, binds to matrix adhesions in a force-dependent manner, promoting cell spreading, adhesion dynamics, and calcium entry in normal but not in most cancer cells tested except some glioblastoma lines. A linker domain in Piezo1 is needed for binding to adhesions, and overexpression of the domain blocks Piezo1 binding to adhesions, decreasing adhesion size and cell spread area. Thus, we suggest that Piezo1 is a previously unidentified component of focal adhesions in nontransformed cells that catalyzes adhesion maturation and growth through force-dependent calcium signaling, but this function is absent in most cancer cells.

PIEZO1 and PECAM1 interact at cell-cell junctions and partner in endothelial force sensing

“…PIEZO1 stimulation straightens CDH5 junctions and its depletion inhibits stretch-evoked remodelling 45 , 46 . PIEZO1 also has roles in focal adhesions 30 , 77 , to which radial actin is attached, consistent with a remodelling role of PIEZO1. Although our data and that of other investigators support roles for PIEZO1 as an enabler of junctional remodelling, whether this results in tighter or weaker junctions (less or more permeability) may depend on context as PIEZO1 depletion enhances or suppresses vascular permeability in vivo 42 , 43 .…”

Membrane curvature governs the distribution of Piezo1 in live cells

“…S5c ). While this high Piezo1 level may resemble the local density of Piezo1 at specific cellular regions such as focal adhesion sites 27 , we wonder whether the observed mechanical effect on membrane protrusions can be of general physiological relevance. To answer this question, we compared the number of filopodia on MEFs dissected from wild type (WT) or Piezo1 heterozygous (Het.)…”

“…While the structure and activation of individual Piezo1 channels have been extensively studied, the dynamics and distribution of the channel within a cell are only starting to be explored 19 , 21 , 25 , 27 . In addition, it is unclear whether the Piezo1 structures determined in vitro recapitulate its nanoscale conformations in living cells 7 , 8 , 10 , 11 .…”

“…Several recent studies highlighted a preferential subcellular distribution of Piezo1: First, a polarized distribution of Piezo1 towards the rear of migrating keratinocytes plays a crucial role in controlling the speed of wound healing 28 . Additionally, Piezo1 has been found to enrich at subcellular structures that are important for mechanotransduction, such as focal adhesion sites 27 , 29 and T-tubules of cardiomyocytes 30 , 31 . Lastly, Piezo1 has been reported to preferentially localize to the intercellular bridge during cytokinesis 32 , and to the biconcave ‘dimples’ in red blood cells 19 , 21 .…”

PIEZO1 regulates leader cell formation and cellular coordination during collective keratinocyte migration

“…The Rho family of small GTPases, which includes the small molecules Rac1 and RhoA, play several roles during collective migration - regulating cell polarization, intercellular coordination of cellular movement, and leader cell initiation ( Das et al (2015) ; Omelchenko et al (2003) ; Reffay et al (2014) ; Zegers and Friedl (2014) ). Previous work has linked PIEZO1-mediated Ca 2+ influx to impacting both focal adhesion dynamics ( McHugh et al (2012) ; Li et al (2014) ; Yao et al (2022) ) as well as Rac1 and RhoA levels. PIEZO1’s effect on small GTPases has been shown to affect migration in both neural crest cells ( Canales Coutiño and Mayor (2021) ) and cancer cells ( Kim et al (2022) ), Cadherin remodeling in lymphatic endothelial cells ( Miroshnikova et al (2021) ), and macrophage mechanotransduction in iron metabolism ( Ma et al (2021) ).…”