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McCusker, D.

Publications and source records attributed to McCusker, D..

2 recordsLinked to original sources

Two RhoGEF isoforms with distinct localisation act in concert to control asymmetric cell division

Cytokinesis is essential for the partitioning of cellular contents into daughter cells. It relies on the formation of an acto-myosin contractile ring, whose constriction induces the ingression of the cleavage furrow between the segregated chromatids. Rho1 GTPase and its RhoGEF (Pbl) are essential for this process as they drive the assembly and constriction of the contractile ring. However, how Rho1 is regulated to sustain efficient furrow ingression while maintaining correct furrow position remains poorly defined. Here, we show that during asymmetric division of Drosophila neuroblasts, Rho1 is controlled by two Pbl isoforms with distinct localisation. Spindle midzone- and furrow-enriched Pbl-A focuses Rho1 at the furrow to sustain efficient ingression, while Pbl-B pan-plasma membrane localization promotes the broadening of Rho1 activity and the subsequent enrichment of cortical myosin. This enlarged zone of Rho1 activity becomes essential to adjust furrow position during ingression, thereby preserving correct daughter cell size asymmetry. Our work highlights how the use of isoforms with distinct localisation patterns provides robustness to an essential process.

cell biology↗

Avidity-driven polarity establishment via multivalent lipid-GTPase module interactions

While Rho GTPases are indispensible regulators of cellular polarity, the mechanisms underlying their anisotropic activation at membranes have been elusive. Using the budding yeast Cdc42 GTPase module, which includes a Guanine nucleotide Exchange Factor (GEF) Cdc24 and the scaffold Bem1, we find that avidity generated via multivalent anionic lipid interactions is a critical mechanistic constituent of polarity establishment. We identify Cationic-enriched Lipid Interacting Clusters (CLICs) in Bem1 that drive the interaction of the scaffold-GEF complex with anionic lipids at the cell pole. This interaction increases lipid acyl chain ordering, thus contributing to membrane rigidity and feedback between Cdc42 and the membrane environment. Sequential mutation of the Bem1 CLIC motifs, PX domain and the PH domain of Cdc24 lead to a progressive loss of cellular polarity stemming from defective Cdc42 nanoclustering on the plasma membrane and perturbed signaling. Our work demonstrates the importance of avidity via multivalent anionic lipid interactions in the spatial control of GTPase activation.

cell biology↗