Backround and significance

Living cells display an overwhelming capacity to assemble microscopic structures capable of performing complex sensory and motor activities. These protein-based machines enable cells to carry out coordinated processes that sustain life. A major task of living cells is the gathering of information about their environment by interactions with their surroundings and executing specific signaling processes across the membrane. These processes had a crucial role in the transition from single-celled organisms to metazoan life, over 4,000 million years ago, a process that also drives the development of a fertilized egg into a multi-cellular organism. This transition required mechanisms to precisely regulate and maintain the spatial position of individual cells and molecules of the extracellular world. This precision and specificity of cellular positioning requires sensitive and accurate environmental sensing‖ mechanisms, which enable cells to constantly obtain positional information‖ about neighboring cells and extracellular matrices, and consequently activate multiple signaling pathways that, in concert, initiate, drive and regulate cellular responses. These in turn affect nearly all facets of the cell‘s life, ranging from alterations in multiple cellular activities, to the modulation of local cellular interactions, induction of directed cell migration, and changes in cell proliferation, survival and gene expression programs. During the last funding period, researchers at Uni-HD and associated institutions pioneered methods and tools to quantitatively assess functional elements of cellular microenvironments in cell signaling. For example, precise spacing in integrin and cadherin clustering was identified as a trigger of adhesion-based signaling events (Fig. 2) in different primary hematopoietic stem cells, cell lines and neurons (Spatz, Pollerberg). GPCR signaling via a MAP kinase cascade was shown to occur via intracellular gradients of effector kinase activity emitted by localized signaling centers at the plasma membrane (Knop). Rho-signaling based hysteresis was demonstrated to be involved in the cell response to time-dependent substrate stiffness (Schwarz). Mechanosensing of cells and malaria parasites were quantitatively investigated using tunable hydrogels and mechanically confined microenvironments (Tanaka, Frischknecht, Spatz). These examples underscore the fascinating possibilities that are now available to explore critical organizational constraints for the modulation of active signaling processes.

 

This EcTop will bundle expertise of groups working on a wide range of different signaling processes and who will benefit greatly from better and well adopted methods to control the structural, physical and chemical parameters of the microenvironments that induce the particular biological processes they investigate. This includes labs that work on signal transduction in yeast (Knop), groups working on signal transduction processes in the context of development (Steinbeisser, Wittbrodt, Pollerberg), on the guidance of single neurons (Pollerberg, Engel), and signaling in host – pathogen interactions (Frischknecht, Fackler). These researchers will team up with experts in single molecule imaging (Herten), automated screening and image analysis (Erfle), Rohr), biophysical and computational methods (Garcia, Hufnagel, Nedelec, Schwarz, Spatz, Tanaka), and generation of artificial matrices (Spatz, Tanaka). The created crossdisciplinary consortium will provide new opportunities to gain a quantitative understanding of how signaling pathways as initiated by the microenvironment lead to complex cell behavior.