Journal
EUROPEAN JOURNAL OF CELL BIOLOGY
Volume 95, Issue 1, Pages 1-14Publisher
ELSEVIER GMBH, URBAN & FISCHER VERLAG
DOI: 10.1016/j.ejcb.2015.10.002
Keywords
Talin; PIP2; uPAR; Focal adhesion; Molecular clutch; Mechanotransduction; AFM
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Funding
- Italian Association for Cancer Research (AIRC)
- Cariplo foundation
- Italian Ministry of University and Research, MIUR, through the National Funding for Basic Research (FIRB)
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The molecular clutch (MC) model proposes that actomyosin-driven force transmission permits integrin-dependent cell migration. To investigate the MC, we introduced diverse talin (TLN) and integrin variants into Flp-In (TM) T-Rex (TM) HEK293 cells stably expressing uPAR. Vitronectin variants served as substrate providing uPAR-mediated cell adhesion and optionally integrin binding. This particular system allowed us to selectively analyse key MC proteins and interactions, effectively from the extracellular matrix substrate to intracellular f-actin, and to therewith study mechanobiological aspects of MC engagement also uncoupled from integrin/ligand binding. With this experimental approach, we found that for the initial PIP2-dependent membrane/TLN/f-actin linkage and persistent lamellipodia formation the C-terminal TLN actin binding site (ABS) is dispensable. The establishment of an adequate MC-mediated lamellipodial tension instead depends predominantly on the coupling of this C-terminal TLN ABS to the actomyosin-driven retrograde actin flow force. This lamellipodial tension is crucial for full integrin activation eventually determining integrin-dependent cell migration. In the integrin/ligand-independent condition the frictional membrane resistance participates to these processes. Integrin/ligand binding can also contribute but is not necessarily required. (C) 2015 Elsevier GmbH. All rights reserved.
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