PAK4 mediates morphological changes through the regulation of GEF-H1
Abstract
Precise spatial and temporal regulation of Rho GTPases is required in controlling F-actin-based changes in cell morphology. The molecular mechanisms through which microtubules (MTs) modulate the activity of RhoGTPases and regulate the actin cytoskeleton are unclear. Here we show that p21-activated-kinase 4 (PAK4) mediates morphological changes through its association with the Rho-family guanine nucleotide exchange factor (GEF), GEF-H1. We show that this association is dependent upon a novel GEF-H1 interaction domain (GID) within PAK4. Further, we show that PAK4-mediated phosphorylation of Ser810 acts as a switch to block GEF-H1-dependent stress fiber formation while promoting the formation of lamellipodia in NIH-3T3 cells. We found that the endogenous PAK4-GEF-H1 complex associates with MTs and that PAK4 phosphorylation of MT-bound GEF-H1 releases it into the cytoplasm of NIH-3T3 cells, which coincides with the dissolution of stress fibers. Our observations propose a novel role for PAK4 in GEF-H1-dependent crosstalk between MTs and the actin cytoskeleton.
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GEF-H1 activation results from disruption of the GEF-H1:dynein complex by G-protein subunits in the absence of microtubule depolymerization.
“Our results suggest a model where GEF-H1 activation results from disruption of the GEF-H1:dynein complex by G-protein subunits in the absence of microtubule depolymerization 6,7 .”
From Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1 (2014) · cites this paper as [7]
Nocodazole-induced microtubule depolymerization potently activates GEF-H1.
“Nocodozole-induced microtubule depolymerization potently activates GEF-H1 (refs 5-7), thus GEF-H1 activity during mitosis may be a consequence of the change in microtubule dynamics during the reorganization of stable interphase microtubules into the mitotic spindle 36 .”
From Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1 (2014) · cites this paper as [7]
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Targeting and transport: How microtubules control focal adhesion dynamics
Stehbens, S., & Wittmann, T. (2012) · Journal of Cell Biology · doi:10.1083/jcb.201206050 · Cited by 244 · see citing works
Microtubules regulate GEF-H1 in response to extracellular matrix stiffness
Heck, J. N., Ponik, S. M., Garcia-Mendoza, M. G., Pehlke, C. A., Inman, D. R., Eliceiri, K. W., & Keely, P. J. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-10-0876 · Cited by 96 · see citing works
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Tonami, K., Kurihara, Y., Arima, S., Nishiyama, K., Uchijima, Y., Asano, T., Sorimachi, H., & Kurihara, H. (2011) · Journal of Cell Science · doi:10.1242/jcs.072561 · Cited by 46 · see citing works
- Authors
- Callow, M. G., Zozulya, S., Gishizky, M. L., Jallal, B., & Smeal, T.
- Affiliations
- SUGEN Incorporated, 230 East Grand Avenue, South San Francisco, CA 94080, USA
- Corresponding author
- Smeal, Tod
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2005-05-01
- Volume
- 118
- Issue
- 9
- Pages
- 1861-1872
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2127080020
- Cited by
- 169
- References
- 1
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 16 · 2016: 8 · 2015: 11 · 2014: 12 · 2013: 14 · 2012: 19
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- PAK4, GEF-H1, Rho GTPases, microtubules, actin cytoskeleton, cell morphology, stress fiber formation, lamellipodia, NIH3T3 cells
- MeSH terms
- Actins, Amino Acid Sequence, Animals, Cell Line, Cloning, Molecular, Cytoplasm, Cytoskeleton, DNA, Gene Expression Regulation, Genetic Vectors, Glutathione Transferase, Humans, Microscopy, Fluorescence, Microtubules, Models, Biological, Models, Genetic, Molecular Sequence Data, Mutation, Peptides, Phosphorylation, Plasmids, Protein Binding, Serine, Substrate Specificity, Time Factors, Transfection, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Biotinylation, GTP Phosphohydrolases, Guanine Nucleotide Exchange Factors, rho GTP-Binding Proteins, rac GTP-Binding Proteins, NIH 3T3 Cells, Mice, p21-Activated Kinases, Rho Guanine Nucleotide Exchange Factors
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