10th Annual Symposium
Physics of Cancer
Leipzig, Germany
September 25-27, 2019
Invited Talk
Dissecting cell migration and mechanics by systematic gene editing approaches
Klemens Rottner
Helmholtz Centre for Infection Research, Inhoffenstraße 7 38124 Braunschweig, Germany
Contact:  | Website
The core interest of my lab is to dissect the signalling pathways and downstream molecular mechanisms driving the formation of actin-based cell edge protrusions. Noteworthy, the same pathways are utilized by diverse pathogens to induce their own uptake into cells.
In this talk, I will focus on signalling through Rac and related small GTPases such as Cdc42 and RhoG, and in particular concerning their relative impact on the regulation of WAVE Regulatory Complex (WRC), which is crucial for the generation of branched actin filament networks in lamellipodia and membrane ruffles. Starting from recently published work on the genetic removal of the Sra-1 and PIR121 subunits of WRC, which constitute direct interaction surfaces with Rac, we are now extending our efforts to characterize interaction nodes of various upstream GTPases with WRC and other Arp2/3 complex activators operating at the plasma membrane. For instance, novel results will be discussed, which were obtained from characterizing a cell line lacking both Sra-1/PIR121 and their upstream regulators Rac1/2/3. This line in combination with re-introduction of constitutively active WRCs allowed us to decipher potential additional inputs to WRC regulation, in a fashion separable from Rac-mediated WRC activation in spite of the latter remaining obligatory for WRC activation.
Moreover, in complementary efforts to genetically target the Sra-1/PIR121-interactor Nap1, and its mostly hematopoietic counterpart Hem1, in migrating B16-F1 melanoma and fibroblast cells, we have found not only that Nap1 removal can cause a compensatory upregulation of Hem1, which occurs to differential extent in distinct cell lines, but also that Nap1/Hem1 double-null cell lines can be stimulated to form lamellipodia-like structures displaying specific but significant differences to canonical lamellipodia. A detailed characterization of these structures will be provided, and resulting implications for their role in cell edge dynamics and mechanics discussed.
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