Cellular functions of GEF-H1, a microtubule-regulated Rho-GEF: is altered GEF-H1 activity a crucial determinant of disease pathogenesis?
Abstract
The Rho guanine nucleotide exchange factor GEF-H1 is uniquely regulated by microtubule binding and is crucial in coupling microtubule dynamics to Rho-GTPase activation in a variety of normal biological situations. Here, we review the roles of GEF-H1 in epithelial barrier permeability, cell motility and polarization, dendritic spine morphology, antigen presentation, leukemic cell differentiation, cell cycle regulation, and cancer. GEF-H1 might also contribute to pathophysiological signaling involved in leukemias, and in cancers associated with mutated p53 tumor suppressor gene, epithelial and endothelial cell dysfunction, infectious disease, and cardiac hypertrophy. We suggest that GEF-H1 could be a novel therapeutic target in multiple human diseases.
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GEF-H1 is sequestered on microtubules in an inactive form and becomes active upon release from microtubules.
“This effect depends on the RhoA activator guanine nucleotide exchange factor H1 (GEF-H1), which is sequestered on microtubules in an inactive form, but becomes active upon release from microtubules 18-22 .”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [20]
Microtubule-destabilizing agents activate GEF-H1 by inducing its unbinding from microtubules.
“As microtubule-destabilizing agents activate GEF-H1 by inducing its unbinding from microtubules 18-21”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [20]
RhoA activation by microtubule-destabilizing agents depends on GEF-H1.
“This effect depends on the RhoA activator guanine nucleotide exchange factor H1 (GEF-H1), which is sequestered on microtubules in an inactive form, but becomes active upon release from microtubules 18-22 .”
From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [20]
GEF-H1 is a molecule that binds microtubules and activates the small GTPase RhoA.
“GEF-H1 is one of these molecules that, in turn, actives a small GTPase referred to as RhoA [42].”
From Expression of Tau Produces Aberrant Plasma Membrane Blebbing in Glial Cells Through RhoA-ROCK-Dependent F-Actin Remodeling (2016) · cites this paper as [42]
GEFH1 is a critical microtubule-regulated activator of Rho signaling pathways.
“GEFH1; also known as Arhgef2 or Lfc), a critical microtubule-regulated activator of Rho signaling pathways.”
From Structural basis of microtubule-mediated signal transduction (2026) · cites this paper as [11]
Human GEFH1 is a multidomain protein belonging to the Dbl homology family of Rho-GTPase activators.
“Human GEFH1 is a multidomain protein belonging to the diffuse B cell lymphoma (Dbl) homology family of Rho-GTPase activators.”
From Structural basis of microtubule-mediated signal transduction (2026) · cites this paper as [11]
Cites
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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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Structural basis of microtubule-mediated signal transduction
Choi, S. R., Blum, T. B., Giono, M., Roy, B., Vakonakis, I., Schmid, D., Oelgarth, N., Ranganathan, A., Gossert, A. D., Shivashankar, G. V., et al. (2026) · Cell · doi:10.1016/j.cell.2025.11.011 · Cited by 14 · see citing works
Neutrophil mechanotransduction: A GEF to sense fluid shear stress
Niethammer, P. (2016) · Journal of Cell Biology · doi:10.1083/jcb.201609101 · Cited by 6 · see citing works
Meiring, J. C. M., Mahapatra, V., Liu, R., Gravett, M. S. C., Morren, D., Saunders, H. A. J., Choi, S. R., Pelster José, A., Karhanova, A., Metallidou, I., et al. (2026) · Nature Cell Biology · doi:10.1038/s41556-026-02079-4
Asensio‐Juárez, G., Pérez‐Díaz, R., Ramos‐Solano, H., Garrido‐Casado, M., Talayero, V. C., & Vicente‐Manzanares, M. (2026) · Molecular Oncology · doi:10.1002/1878-0261.70333
- Authors
- Birkenfeld, J., Nalbant, P., Yoon, S.-H., & Bokoch, G. M.
- Affiliations
- University of Duisburg-Essen (DE)
- Scripps Research Institute (US)
- Corresponding author
- Bokoch, Gary M.
- Venue
- Trends in Cell Biology
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 18
- Issue
- 5
- Pages
- 210-219
- ISSN
- 0962-8924 (ISSN-L)
- OpenAlex
- W1970173720
- Cited by
- 190
- References
- 1
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 5 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 9 · 2019: 9 · 2018: 14 · 2017: 9 · 2016: 5 · 2015: 2 · 2014: 11 · 2013: 17 · 2012: 22
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- 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 › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- GEF-H1, RhoGEF, microtubule binding, Rho GTPase activation, microtubule dynamics, epithelial permeability, cell motility, cell polarization, dendritic spine morphology, antigen presentation, leukemia cell differentiation, cell cycle regulation, cancer, TP53 mutation, endothelial dysfunction, cardiac hypertrophy, therapeutic target
- MeSH terms
- Animals, Cell Differentiation, Cell Movement, Cell Transformation, Neoplastic, Epithelium, Gene Expression Regulation, Humans, Microtubules, Models, Biological, Mutation, Neoplasms, Genes, Tumor Suppressor, Antigen Presentation, Guanine Nucleotide Exchange Factors, rho GTP-Binding Proteins, Rho Guanine Nucleotide Exchange Factors
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