Final Report Summary - INCEL (Revealing the molecular architecture of integrin mediated cell adhesion)
Cell adhesions play an important role in the organization, growth, maturation, and function of living cells. Interaction of cells with the extracellular matrix (ECM) also play an essential role in a variety of disease states, including tumor formation and metastasis, inflammation, and repair of wounded tissues At the cellular level, many of the biological responses to external stimuli originate at adhesion loci, such as focal adhesions (FAs), which link cells to the ECM or to their neighbors. Cell adhesion is mediated by receptor proteins, such as cadherins and integrins. The accurate molecular composition, dynamics and signaling activity of these adhesion assemblies determine the specificity of adhesion-induced signals and their effects on the cell. However, characterization of the molecular architecture of FAs is highly challenging: it is still unclear how these molecules function together, how they are recruited to the adhesion site, how they are turned-over, and how they function in vivo. In the course of this project, we studied the structure of integrin-mediated cell adhesion. We applied state-of-the-art technologies such as fluorescent light microscopy in conjunction with cryo-electron tomography and modulation of the underlying matrix using micro- and nanopatterned adhesive surfaces to reveal the 3D molecular organization of the adhesion machinery.
Our analysis showed the molecular basis of interactions between the actin cytoskeleton and the membrane domain of the adhesion machinery. In particular this work has already indicated that the actin cytoskeleton interacts with the integrin receptor through a layer of macromolecular complexes. Thus, the force applied to the adhesion machinery is mediated via regulators and not by a direct interaction between the cytoskeleton and the integrin receptors. Moreover, we have able to provide the first insight into the adhesion architecture in platelets in health and disease. Namely, in the course of this work we identify the alteration of platelets cytoskeleton in Glanzmann Thrombosthenia platlets . In sumarry, our findings clarify the internal architecture of adhesion machinery at molecular resolution, and provide new insights into their scaffolding and mechanosensory functions.
Our analysis showed the molecular basis of interactions between the actin cytoskeleton and the membrane domain of the adhesion machinery. In particular this work has already indicated that the actin cytoskeleton interacts with the integrin receptor through a layer of macromolecular complexes. Thus, the force applied to the adhesion machinery is mediated via regulators and not by a direct interaction between the cytoskeleton and the integrin receptors. Moreover, we have able to provide the first insight into the adhesion architecture in platelets in health and disease. Namely, in the course of this work we identify the alteration of platelets cytoskeleton in Glanzmann Thrombosthenia platlets . In sumarry, our findings clarify the internal architecture of adhesion machinery at molecular resolution, and provide new insights into their scaffolding and mechanosensory functions.