Graduiertenkolleg 1167 - P13-2: RhoGEFs and associated kinases as regulators of actin dynamics and actin dependent processes in T-cells and neurons

Actin filaments are key components of cell-cell and cell-matrix contacts in both the immune and nervous systems. The dynamic regulation of actin filaments and actin filament-associated transport is critical for the formation and maintenance of synapses and cellular processes such as migration, adhesion und secretion. We (OS) have previously shown that the serine/threonine kinase Ndr2 is a modulator of endosomal transport and integrin-dependent differentiation of neurons. How Ndr2 signals to regulate actin dependent functions on a molecular level remains unclear. Genetic evidence suggests an interaction of Ndr2 with the kinases PAK and ROCK, which mediate signals from Rho GTPases to the actin cytoskeleton. This signalling pathway is controlled by Rho-GTPase guanine nucleotide exchange factors (RhoGEFs), which determine signal specificity and are involved in pathway selection. In this context, we (KDF) have characterized RhoGEF-dependent signalling pathways that control actin-mediated cellular functions in T-cells. Here, we will combine our expertise in actin regulation in T cells and neuronal signalling to use genetic, molecular and cell based approaches to determine, how Ndr2 modulates PAK or ROCK activities or if Ndr2 activity itself is regulated by PAK or ROCK. Once the kinases upstream or downstream of Ndr2 are identified, we will determine the role of specific RhoGEFs in Ndr2 signalling to better understand how an actin regulating signalling network is orchestrated. Finally, to determine if the pathways are conserved in different cell types, the analysis will be performed in T-cells and neurons.