Tyler, J.J., Davidson, A. orcid.org/0000-0003-1783-7299, Poxon, M.E. et al. (4 more authors) (2025) A role for class I p21-activated kinases in the regulation of the excitability of the actin cytoskeleton. Journal of Cell Science, 138 (12). jcs263763. ISSN 0021-9533
Abstract
The p21-activated kinases (PAKs) are involved in a range of functions, including the regulation of the actin cytoskeleton. However, although many PAK substrates identified have been implicated in the regulation of the actin cytoskeleton, a coherent picture of the total effect of PAK activation on the state of the actin cytoskeleton is unclear. Here, we show that, in mouse embryonic fibroblasts, inhibition of class I PAK kinase activity by small-molecule inhibitors leads to the constitutive production of the phosphoinositide phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] on the ventral surface of the cell. The formation of patches of PI(3,4,5)P3 remodels the actin cytoskeleton and polarises the cell. From the overexpression of truncated and mutated PAK1 and PAK2 constructs, as well as an in vitro model of PAK activation, we propose that this is driven by a hyper recruitment of class I PAK and PAK-binding partners. This aberrant production of PI(3,4,5)P3 suggests that, by limiting its own recruitment, the kinase activity of class I PAKs acts to downregulate phosphoinositide 3-kinase (PI3K) activity, further highlighting class I PAKs as regulators of PI3K activity and therefore the excitability of the actin cytoskeleton.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2025. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
Keywords: | PAK; Actin; Excitability; PI3K; Actin waves |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Funding Information: | Funder Grant number BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/W006049/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 30 Jun 2025 13:46 |
Last Modified: | 30 Jun 2025 13:46 |
Status: | Published |
Publisher: | The Company of Biologists |
Refereed: | Yes |
Identification Number: | 10.1242/jcs.263763 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:228537 |