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Gradients Of Rac1 Nanoclusters Support Spatial Patterns Of Rac1 Signaling

Research conducted by Mathieu Coppey – Light-based Observation and Control of Cellular Organization (CNRS/UPMC/Institut Curie) Team – published in Cell Reports

Cells are platted on crossbow adhesive micropatterns to normalize their shapes. Left: nanoclusters distribution, middle: local immobilization density, right: Rac1 activity (FRET biosensor).
Cells are platted on crossbow adhesive micropatterns to normalize their shapes. Left: nanoclusters distribution, middle: local immobilization density, right: Rac1 activity (FRET biosensor).

Abstract
“The dynamics of the cytoskeleton and cell shape relies on the coordinated activation of RhoGTPase molecular switches. Among them, Rac1 participates to the orchestration in space and time of actin branching and protrusion/retraction cycles of the lamellipodia at the cell front during mesenchymal migration. Biosensor imaging has revealed a graded concentration of active GTP-loaded Rac1 in protruding regions of the cell. Here, using single molecule imaging and super-resolution microscopy, we reveal an additional supramolecular organization of Rac1. We find that, similarly to H-Ras, Rac1 partitions and is immobilized into nanoclusters of 50-100 molecules each. These nanoclusters assemble due to the interaction of the polybasic tail of Rac1 with the phosphoinositide lipids PIP2 and PIP3. The additional interactions with GEFs, GAPs, downstream effectors, and possibly other partners are responsible for an enrichment of Rac1 nanoclusters in protruding regions of the cell. Using optogenetics and micropatterning tools, we find that activation of Rac1 leads to its immobilization in nanoclusters and that the local level of Rac1 activity matches the local density of nanoclusters. Altogether, our results show that subcellular patterns of Rac1 activity are supported by gradients of signaling nanodomains of heterogeneous molecular composition, which presumably act as discrete signaling platforms. This finding implies that graded distributions of nanoclusters might encode spatial information.”

Gradients Of Rac1 Nanoclusters Support Spatial Patterns Of Rac1 Signaling
Amanda Remorino, Simon De Beco, Fanny Cayrac, Fahima Di Federico, Gaetan Cornilleau, Alexis Gautreau, Maria Carla Parrini, Jean-Baptiste Masson, Maxime Dahan, Mathieu Coppey