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Ubiquitylation-dependent Rap2 activation regulates lamellipodia dynamics during cell migration
Andrew Neumann1, Revathi Sampath1,2, Emily Mayerhofer1
1Department of Cell and Developmental Biology, School of Medicine , University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Journal of Cell Science
|November 7, 2025
Summary
Rap2 protein is recruited to cell structures called lamellipodia, where it regulates actin dynamics to aid cell migration. This process requires ubiquitylation for Rap2 activation and targeting to the cell membrane.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cell migration relies on actin cytoskeleton dynamics and cell polarity.
- Rap2, a Ras GTPase, localizes to the lamellipodium via ubiquitylation by Rab40/CRL5.
- The precise function and targeting mechanism of Rap2 in cell migration were unclear.
Purpose of the Study:
- To elucidate the function of Rap2 in cell migration.
- To understand how Rap2 is targeted to the lamellipodium.
- To investigate the role of ubiquitylation in Rap2 activation and localization.
Main Methods:
- Genetic and pharmacological approaches were employed.
- Investigated Rap2 recruitment to lamellipodia ruffles.
- Analyzed Rap2's interaction with RhoA and ARHGAP29.
- Examined the requirement of Rab40/CRL5-dependent ubiquitylation for Rap2 activation and membrane targeting.
Main Results:
- Rap2 inhibits RhoA, likely via ARHGAP29, in retracting lamellipodia ruffles.
- Rap2 regulates lamellipodia dynamics, thereby facilitating cell migration.
- Rab40/CRL5-dependent ubiquitylation is essential for guanine-nucleotide-exchange factor (GEF)-dependent Rap2 activation.
- Ubiquitylation is necessary for Rap2 targeting to the lamellipodium membrane.
Conclusions:
- Rap2 plays a crucial role in regulating lamellipodia actin dynamics during cell migration.
- Rab40/CRL5-mediated ubiquitylation uniquely activates and targets Rap2 to the lamellipodium.
- This study reveals a novel mechanism of Rap2 regulation impacting cell motility.
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