Project description
A dial rather than a switch for cellular 'stickiness' may lead to more precise control
A cell's ability to stick to molecules in its local environment plays an important role in processes from normal embryonic development and wound healing to inflammation and cancer metastasis. Integrins are a large family of adhesion receptor molecules that span the cell membranes and mediate dynamic remodelling of the cytoskeleton during adhesion and migration. The first step is integrin activation via a complicated and still unclear process. The EU-funded PoInt project is shedding light on integrin activation by combining studies of single molecules, molecular complexes, multi-cellular constructs and organised 3D tissue cultures. The ultimate goal is more effective therapies with fewer side effects for numerous conditions characterised by cell adhesion gone rogue.
Objective
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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Funding Scheme
ERC-SyG - Synergy grantHost institution
80539 Munchen
Germany