Cells frequently change their shape and their attachment to the environment in order to move or to adopt specialized structures in a tissue. These events are driven by coordinated changes of the cytoskeleton and are fundamental during embryonic development, immune surveillance or wound repair. Specificity of Rho GTPase function is achieved by the huge family of RhoGEF and RhoGAP regulatory proteins.
We aim to study in detail how these proteins couple Rho activity to specific environmental cues and functional contexts in a cell. Our lab also investigates the dynamics of local Rho signaling complex formation at the membrane at a single molecule level. Insights into this spatio-temporal regulation of Rho signaling will provide a deeper understanding of morphodynamic processes in cells and organisms, both in normal and disease settings.
Rho family GTPase proteins are the master regulators of the cytoskeleton, controlling fundamental morphogenetic processes ranging from embryonic development to wound repair. We investigate how the signaling function of Rho GTPases is regulated in space and time and how its specificity is achieved.
Rho activity is controlled by three factors: GTPase activating proteins (RhoGAPs) and guanine nucleotide exchange factors (RhoGEFs), which drive the GDP/GTP activity cycle, and guanine nucleotide dissociation inhibitors (GDIs), which keep the lipid-anchored GTPases in the cytosol. Our genome encodes as many as 145 RhoGEFs and GAPs. These multi-domain proteins can target the GTPases to distinct cellular locations and act as scaffolds to connect to upstream cues, further signaling programs and downstream effectors.
We have previously assembled a complete cDNA library of all RhoGEFs and GAPs and performed a systematic analysis of their interactors, localization and substrate specificities. Combining advanced microscopy with cell biology and work in model organisms, we now exploit this unique dataset and toolbox to characterize novel RhoGEFs and GAPs in different signaling contexts. These currently include: control of cell-cell adhesion, guidance receptor and G protein coupled receptor signaling, with implications in muscle development, endocrine signaling and neural cancer development.
Another research interest is to analyze the membrane interaction dynamics of the lipid-anchored Rho proteins and how it is regulated. How on membranes Rho signaling complexes are formed, maintained and disassembled is not well studied. We use state-of-the-art imaging to elucidate such modes of temporal Rho signal regulation.