WASP restricts active Rac to maintain cells’ front-rear polarisation
Preprint posted on April 10, 2019 https://www.biorxiv.org/content/10.1101/602425v1
Rho family GTPases (Cdc42, Rac1, and Rho) are the major regulators of cell polarity and migration. They coordinate the formation of actin protrusions (lamellipodia, filopodia, pseudopods) by controlling the activity of WASP family proteins, which are the main regulators of actin polymerization1. The active form of Rho GTPases specifically binds to the CRIB domain (conserved in most organisms) in WASPs, which is thought to control its function. Although WASP and SCAR/WAVE’s role in pseudopod formation and cell migration have been studied extensively, how cells control their spatial and temporal localization and function has not been completely understood and remains controversial. Prior work by the group successfully demonstrated that WASP deletion causes reduced cell migration in Dictyostelium cells, as a result of a defect in rear retraction2.
In this study, the authors demonstrate how WASP maintains cell polarity to regulate migration. A key point highlighted in the paper is the significance of binding of active Rho GTPases to WASP (through its CRIB motif) in regulating its function.
The authors demonstrate that WAVE and active “GTP bound” Rac accumulate in the rear of migrating cells upon WASP depletion, creating a nearly bipolar state in spite of a morphologically distinct leading edge in Dictyostelium cells. As a result of the “bipolar” state of WASP depleted cells, F-actin-rich structures were formed at both ends during migration. This is clearly an unexpected role of WASP in maintaining front-rear polarity by limiting the fraction of plasma membrane associated with active Rac.
Further, the authors convincingly illustrate that WASP does not require binding to active Rac in order to localize to clathrin-coated pits or to recruit Arp2/3 complex & F-actin polymerization. However, WASP binding to active Rac through the CRIB domain is indispensable for the maintenance of front-rear polarity of Rac during migration and also for the homeostasis of active Rac levels in the cell.
This reveals that a functional CRIB motif in WASP is not an absolute requirement for WASP to carry out all of its described functions and appears to be context-dependent; moreover, it suggests a potential small GTPase-independent regulatory mode.
Importance and Future questions
Findings from this study bring a new perspective to the interaction between small GTPase (specifically Rac) and WASP family in regulating cell polarity and controlling cell migration. As discussed by the authors, a direct interaction of active Rac with WASP is not a requirement for recruitment of Arp2/3, actin polymerization, and clathrin-mediated endocytosis. However, WASP needs to physically interact with upstream active Rac via its CRIB motif for the formation of pseudopods in SCAR/WAVE depleted cells. These findings provide new insights into how small GTPases talk to WASPs in the regulation of various cellular processes.
In the future, it would be interesting to explore these aspects:
- How do cells with the bipolar state (where Rac is active in the front and rear) behave under mechanical tension, similar to what they would experience in a tumor environment?
- Is there any evolutionary significance of the CRIB motif and its context-dependent interaction in the regulation of cellular processes?
- Krause, M. & Gautreau, A. Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nature Reviews Molecular Cell Biology 15, 577–590 (2014).
- Davidson, A. J., Amato, C., Thomason, P. A. & Insall, R. H. WASP family proteins and formins compete in pseudopod- and bleb-based migration. The Journal of Cell Biology 217, 701–714 (2018).
Posted on: 21st May 2019Read preprint
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