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: 21 May 2019Read preprint
Also in the cell biology category:
TLR2 Regulates Hair Follicle Cycle and Regeneration via BMP Signaling
Mechano-dependent sorbitol accumulation supports biomolecular condensate
CRISPR-dependent base editing screens identify separation of function mutants of RADX with altered RAD51 regulatory activity
preListscell biology category:in the
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
|List by||Joyce Yu, Katherine Brown|
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
|List by||Alex Eve|
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
|List by||Helen Zenner|
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
|List by||Martin Estermann|
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
|List by||Sergio Menchero et al.|
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
|List by||Nadja Hümpfer et al.|
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
|List by||Osvaldo Contreras|
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
|List by||Alex Eve|
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
|List by||Ana Dorrego-Rivas|
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
|List by||Ana Dorrego-Rivas|
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
|List by||Dey Lab, Samantha Seah|
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
|List by||Yamini Ravichandran|
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
|List by||Maiko Kitaoka et al.|
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
|List by||Paul Gerald L. Sanchez and Stefano Vianello|
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
|List by||Hiral Shah|
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
|List by||Madhuja Samaddar et al.|
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
|List by||Dey Lab|
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
|List by||Sandra Malmgren Hill|
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
|List by||Rob Hynds|
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
|List by||Pablo Ranea Robles|
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
|List by||Dey Lab|
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
|List by||Sandra Franco Iborra|
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
|List by||Joseph Jose Thottacherry|
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
|List by||Dey Lab, Amanda Haage|