WASP restricts active Rac to maintain cells’ front-rear polarization

Amato, C., Thomason, P. A., Davidson, A. J., Swaminathan, K., Ismail, S. , Machesky, L. M. and Insall, R. H. (2019) WASP restricts active Rac to maintain cells’ front-rear polarization. Current Biology, 29(24), pp. 4169-4182. (doi: 10.1016/j.cub.2019.10.036) (PMID:31786060) (PMCID:PMC6926487)

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Efficient motility requires polarized cells, with pseudopods at the front and a retracting rear. Polarization is maintained by restricting the pseudopod catalyst, active Rac, to the front. Here, we show that the actin nucleation-promoting factor Wiskott-Aldrich syndrome protein (WASP) contributes to maintenance of front-rear polarity by controlling localization and cellular levels of active Rac. Dictyostelium cells lacking WASP inappropriately activate Rac at the rear, which affects their polarity and speed. WASP’s Cdc42 and Rac interacting binding (“CRIB”) motif has been thought to be essential for its activation. However, we show that the CRIB motif’s biological role is unexpectedly complex. WASP CRIB mutants are no longer able to restrict Rac activity to the front, and cannot generate new pseudopods when SCAR/WAVE is absent. Overall levels of Rac activity also increase when WASP is unable to bind to Rac. However, WASP without a functional CRIB domain localizes normally at clathrin pits during endocytosis, and activates Arp2/3 complex. Similarly, chemical inhibition of Rac does not affect WASP localization or activation at sites of endocytosis. Thus, the interaction between small GTPases and WASP is more complex than previously thought—Rac regulates a subset of WASP functions, but WASP reciprocally restricts active Rac through its CRIB motif.

Item Type:Articles
Additional Information:Funding was provided by Cancer Research UK grants A15672, A24450, and multidisciplinary grant A20017.
Glasgow Author(s) Enlighten ID:Thomason, Dr Peter and Davidson, Mr Andrew and Machesky, Professor Laura and Insall, Professor Robert and Amato, Clelia and Ismail, Dr Shehab
Authors: Amato, C., Thomason, P. A., Davidson, A. J., Swaminathan, K., Ismail, S., Machesky, L. M., and Insall, R. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Current Biology
ISSN (Online):1879-0445
Published Online:27 November 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Current Biology 29(24):4169-4182
Publisher Policy:Reproduced under a Creative Commons License

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