Unravelling the force-induced dynamics of integrin-based adhesion complexes
Author
Summary, in English
A cell’s ability to sense and respond to mechanical cues from its extracellular environment is essential for maintaining the health of itself and its organism. The mechanical cues a cell encounters include physical forces such as shear, tensile, and compressive forces, as well as cues arising from the mechanical properties of the extracellular matrix (ECM), such as stiffness or composition. Through mechanotransduction, a cell converts these mechanical cues into biochemical signals that control a wide range of functions, such as differentiation, morphogenesis, cell migration, and apoptosis.
integrin-based adhesion complexes (IACs) are one of the primary mechanisms of mechanotransduction. These large protein structures transmit mechanical signals between the ECM and the cell’s actomyosin cytoskeleton. In this thesis we investigate changes in IAC composition in response to externally applied forces and identify and study individual force-sensitive IAC proteins.
To investigate changes in IAC composition in response to varying durations of externally applied forces, we first combined a magnetic bead-based isolation assay with mass spectrometry. This approach revealed dynamic, force-duration-dependent changes in IAC composition. With prolonged force application, IACs transitioned from clathrin-rich structures to more focal adhesion-like structures, and ultimately to structures highly enriched in translational proteins.
Next, we focused our investigation on Sept-7 and Larp1, identified in our studies as highly force-sensitive proteins. We found that Sept-7 influences the stabilization and maturation of IACs and plays a crucial role in ECM sensing and remodeling. While Larp1 is well-documented as a regulator of translation, our studies identify it as a bona fide force-sensitive IAC protein.
Knowledge gained from this thesis advances our understanding of IACs, particularly their dynamic and adaptable responses to mechanical cues. Moreover, it underscores how much more remains to be discovered about these complex and fascinating structures.
integrin-based adhesion complexes (IACs) are one of the primary mechanisms of mechanotransduction. These large protein structures transmit mechanical signals between the ECM and the cell’s actomyosin cytoskeleton. In this thesis we investigate changes in IAC composition in response to externally applied forces and identify and study individual force-sensitive IAC proteins.
To investigate changes in IAC composition in response to varying durations of externally applied forces, we first combined a magnetic bead-based isolation assay with mass spectrometry. This approach revealed dynamic, force-duration-dependent changes in IAC composition. With prolonged force application, IACs transitioned from clathrin-rich structures to more focal adhesion-like structures, and ultimately to structures highly enriched in translational proteins.
Next, we focused our investigation on Sept-7 and Larp1, identified in our studies as highly force-sensitive proteins. We found that Sept-7 influences the stabilization and maturation of IACs and plays a crucial role in ECM sensing and remodeling. While Larp1 is well-documented as a regulator of translation, our studies identify it as a bona fide force-sensitive IAC protein.
Knowledge gained from this thesis advances our understanding of IACs, particularly their dynamic and adaptable responses to mechanical cues. Moreover, it underscores how much more remains to be discovered about these complex and fascinating structures.
Publishing year
2025
Language
English
Publication/Series
Lund University, Faculty of Medicine Doctoral Dissertation Series
Issue
2025:11
Full text
Document type
Dissertation
Publisher
Lund University, Faculty of Medicine
Topic
- Cell and Molecular Biology
- Cancer and Oncology
Keywords
- mechnobiology
- Integrin-based adhesion complexes
- focal adhesions
- fibroblasts
- Larp1
- Sept-7
- Septins
- Mechanotransduction, Cellular
Status
Published
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-8021-664-7
Defence date
7 February 2025
Defence time
13:00
Defence place
Belfragesalen, BMC D15, Klinikgatan 32 i Lund
Opponent
- Ben Goult (Professor)