Cells and force transduction

This thesis studies mechanism involved in propagating force generated at cadherin complexes. The first part of this thesis demonstrates that mechanotransduction at classical cadherin complexes is not only ligand-dependent but also dependent on the respective receptor tyrosine kinase (RTK) binding partner of cadherin. This involvement of RTKs at cadherin complexes is important in propagating force transduction globally, implying that force transduction at cadherin complexes is not restricted to cell-cell junctions but is also propagated globally via the mediation of its respective RTK binding partner. These results suggest that homophilic ligation in trans- and cadherin association with cognate receptor tyrosine kinase in cis comprises a combinatorial, mechano-chemical switch. That is, specific combinations of cadherin, ligand, and RTK is required for force-activated RTK-dependent signaling, activation of cell contractility, and cytoskeletal remodeling at perturbed cadherin adhesions. These findings confirm that cadherins form both homophilic and heterophilic bonds, but homophilic cadherin ligation selectively triggers cadherin-associated RTK signals that mechanically reinforce homophilic, but not heterophilic cadherin adhesions, thereby stabilizing homophilic adhesions and amplifying binding differences. This study demonstrates that this mechano-chemical switch is not governed by cadherin adhesion differences, but requires a specific combination of cadherin ligand in trans- and RTK expression in cis to actuate force transduction signaling on rigid surfaces to propagate force transduction at a global level. For the second part of this study used novel, force-limited nanoscale tension gauges to investigate how force and substrate stiffness guide cellular decision-making during initial cell attachment and spreading on deformable substrates. The well-established dependence of cell traction and spreading on substrate stiffness has been attributed to levels of force exerted on molecular components in focal contacts. The molecular tension gauges used in this study enabled direct estimates of the threshold, pico Newton forces that instructed decision-making at different stages of cell attachment, spreading, and adhesion maturation. These results further confirm that the force thresholds controlling adhesion and spreading transitions depend on substrate stiffness. Reported findings agree semi-quantitatively with a proposed model that attributes rigidity-dependent differences in cell spreading to stiffness-dependent rates of competing biochemical processes

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Bioengineering

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2019

Author dc:creator

• Rahil, Zainab

Contributors dc:contributor

• Leckband, Deborah
• Kong, Hyun Joon
• Wagner-Johnson, Amy
• Underhill, Gregory

• Mechano-transduction, cellular forces

Statement dc:rights

• Copyright 2018 Zainab Rahil

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/102905

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/102905