Binding of GEF-H1 to the Tight Junction-Associated Adaptor Cingulin Results in Inhibition of Rho Signaling and G1/S Phase Transition
Open accessAbstract
The activity of Rho GTPases is carefully timed to control epithelial proliferation and differentiation. RhoA is downregulated when epithelial cells reach confluence, resulting in inhibition of signaling pathways that stimulate proliferation. Here we show that GEF-H1/Lfc, a guanine nucleotide exchange factor for RhoA, directly interacts with cingulin, a junctional adaptor. Cingulin binding inhibits RhoA activation and signaling, suggesting that the increase in cingulin expression in confluent cells causes downregulation of RhoA by inhibiting GEF-H1/Lfc. In agreement, RNA interference of GEF-H1 or transfection of GEF-H1 binding cingulin mutants inhibit G1/S phase transition of MDCK cells, and depletion of cingulin by regulated RNA interference results in irregular monolayers and RhoA activation. These results indicate that forming epithelial tight junctions contribute to the downregulation of RhoA in epithelia by inactivating GEF-H1 in a cingulin-dependent manner, providing a molecular mechanism whereby tight junction formation is linked to inhibition of RhoA signaling.
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The GEFH1 C1 domain does not bind diacylglycerol.
“Prior studies indicate that the GEFH1 C1 domain does not bind diacylglycerol,21”
From Structural basis of microtubule-mediated signal transduction (2026) · cites this paper as [21]
The Introduction describes GEF-H1’s C1 domain and an assay of its binding to the PH domain, but does not address whether C1 binds diacylglycerol. Searches for diacylglycerol, DAG, lipid binding, and phorbol esters found no passage resolving the claim; page numbers were unavailable in our copy. (LLM, conf=0.72)
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Setting up a selective barrier at the apical junction complex
Anderson, J. M., Van Itallie, C. M., & Fanning, A. S. (2004) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2004.01.005 · Cited by 215 · see citing works
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González-Mariscal, L., Tapia, R., & Chamorro, D. (2008) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2007.08.018 · Cited by 759 · see citing works
Tight junctions/adherens junctions: basic structure and function
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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
- Authors
- Aijaz, S., D’Atri, F., Citi, S., Balda, M. S., & Matter, K.
- Affiliations
- University College London (GB)
- University of Geneva (CH)
- Corresponding author
- Balda, Maria S.
- Matter, Karl
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 8
- Issue
- 5
- Pages
- 777-786
- ISSN
- 1534-5807 (ISSN-L)
- OpenAlex
- W2101295963
- Cited by
- 226
- References
- 2
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 10 · 2023: 5 · 2022: 7 · 2021: 15 · 2020: 9 · 2019: 15 · 2018: 13 · 2017: 11 · 2016: 10 · 2015: 4 · 2014: 19 · 2013: 11 · 2012: 15
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, other-oa)
- 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 › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- GEF-H1, cingulin, RhoA, Rho GTPase signaling, tight junctions, guanine nucleotide exchange factor, G1/S transition, epithelial cell proliferation, cell confluence, MDCK cells, epithelial differentiation, cell adhesion
- MeSH terms
- Animals, Base Sequence, Cell Line, DNA, Dogs, Membrane Proteins, Protein Binding, Signal Transduction, G1 Phase, S Phase, Protein Structure, Tertiary, Tight Junctions, Guanine Nucleotide Exchange Factors, rhoA GTP-Binding Protein, RNA Interference, Adaptor Proteins, Signal Transducing
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