Summary
Integrin-mediated adhesion to the extracellular matrix is a prerequisite for the development and homeostasis of multicellular organisms. A hallmark of integrins is that ligand binding requires an “integrin activation” step affecting the shape of the entire molecule is induced by the integrin tail- and actomyosin-binding adaptor proteins talin and kindlin. In a second step, integrins cluster and assemble a gigantic signaling hub, where they integrate biochemical and biophysical signals to achieve their functional output. Due to the lack of combined expertise and suitable technologies, the key steps of integrin activation are still largely unknown and the underlying physical principles still need to be identified. We propose a multifaceted approach combining quantitative single molecule measurements, reconstitution of minimal and cellular adhesion complexes as well as development of multicellular structures and organoids. We propose four aims. In our first aim we will unravel how forces are propagated through the talin-integrin tail bonds and how force-induced integrin shape changes affect signaling. In the second aim we will use novel force spectrometers to determine energy landscapes and the high-resolution structure of fibronectin-integrin complexes. In our third aim we will use in vitro model membranes to test how integrin tail-binding adaptors, cortical F-actin and specific domains of integrins induce integrin clustering. With our fourth aim we will unravel how integrins integrate chemical and biophysical signals during organ development. Using the proposed synergistic approach, we will decipher fundamental principles of cell adhesion biology. Furthermore, our research will result in a better understanding of the fundamental mechanisms regulating adhesion signaling that will allow us to develop strategies to curb adhesion functions without completely blocking integrins, thus limiting the enormous side effects of current interventions.
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| Web resources: | https://cordis.europa.eu/project/id/810104 |
| Start date: | 01-04-2019 |
| End date: | 31-03-2025 |
| Total budget - Public funding: | 7 217 200,00 Euro - 7 217 200,00 Euro |
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Original description
Integrin-mediated adhesion to the extracellular matrix is a prerequisite for the development and homeostasis of multicellular organisms. A hallmark of integrins is that ligand binding requires an “integrin activation” step affecting the shape of the entire molecule is induced by the integrin tail- and actomyosin-binding adaptor proteins talin and kindlin. In a second step, integrins cluster and assemble a gigantic signaling hub, where they integrate biochemical and biophysical signals to achieve their functional output. Due to the lack of combined expertise and suitable technologies, the key steps of integrin activation are still largely unknown and the underlying physical principles still need to be identified. We propose a multifaceted approach combining quantitative single molecule measurements, reconstitution of minimal and cellular adhesion complexes as well as development of multicellular structures and organoids. We propose four aims. In our first aim we will unravel how forces are propagated through the talin-integrin tail bonds and how force-induced integrin shape changes affect signaling. In the second aim we will use novel force spectrometers to determine energy landscapes and the high-resolution structure of fibronectin-integrin complexes. In our third aim we will use in vitro model membranes to test how integrin tail-binding adaptors, cortical F-actin and specific domains of integrins induce integrin clustering. With our fourth aim we will unravel how integrins integrate chemical and biophysical signals during organ development. Using the proposed synergistic approach, we will decipher fundamental principles of cell adhesion biology. Furthermore, our research will result in a better understanding of the fundamental mechanisms regulating adhesion signaling that will allow us to develop strategies to curb adhesion functions without completely blocking integrins, thus limiting the enormous side effects of current interventions.Status
SIGNEDCall topic
ERC-2018-SyGUpdate Date
27-04-2024
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