Cloning and Characterization of GEF-H1, a Microtubule-associated Guanine Nucleotide Exchange Factor for Rac and Rho GTPases
Open accessAbstract
The Rho-related small GTPases are critical elements involved in regulation of signal transduction cascades from extracellular stimuli to cell nucleus and cytoskeleton. The Dbl-like guanine nucleotide exchange factors (GEF) have been implicated in direct activation of these GTPases. Here we have identified a new member of the Dbl family, GEF-H1, by screening a human HeLa cell cDNA library. GEF-H1 encodes a 100-kDa protein containing the conserved structural array of a Dbl homology domain in tandem with a pleckstrin homology domain and is most closely related to the lfc oncogene, but additionally it contains a unique coiled-coil domain at the carboxyl terminus. Biochemical analysis reveals that GEF-H1 is capable of stimulating guanine nucleotide exchange of Rac and Rho but is inactive toward Cdc42, TC10, or Ras. Moreover, GEF-H1 binds to Rac and Rho proteins in both the GDP- and guanosine 5'-3-O-(thio)triphosphate-bound states without detectable affinity for Cdc42 or Ras. Immunofluorescence reveals that GEF-H1 colocalizes with microtubules through the carboxyl-terminal coiled-coil domain. Overexpression of GEF-H1 in COS-7 cells results in induction of membrane ruffles. These results suggest that GEF-H1 may have a direct role in activation of Rac and/or Rho and in bringing the activated GTPase to specific target sites such as microtubules.
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GEF-H1 is associated with microtubules in its inactive state.
“GEF-H1, also known as ARHGEF2 or Lfc in mouse, is associated with microtubules in its inactive state 1 .”
From Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1 (2014) · cites this paper as [1]
The Subcellular Distribution Pattern results (Figs. 7–8; page unavailable) show that GEF-H1 colocalizes with microtubules. They do not establish that microtubule-associated GEF-H1 is inactive. The discussion’s reference to an inactive GDP-bound state concerns Rac, not GEF-H1. (LLM, conf=0.88)
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- Sambrook, J., Fritsch, E. F., and Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd Ed., pp. 8.2-8.85, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 36.
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- Authors
- Ren, Y., Li, R., Zheng, Y., & Busch, H.
- Affiliations
- University of Tennessee Health Science Center (US)
- Baylor College of Medicine (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1998-12
- Volume
- 273
- Issue
- 52
- Pages
- 34954-34960
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2037610353
- Cited by
- 295
- References
- 0
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 13 · 2019: 17 · 2018: 8 · 2017: 14 · 2016: 17 · 2015: 2 · 2014: 11 · 2013: 16 · 2012: 21
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM053943, GM53943)
- 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 transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- GEF-H1, guanine nucleotide exchange factor, Rac GTPase, Rho GTPases, microtubule-associated proteins, Dbl homology domain, pleckstrin homology domain, coiled-coil domain, GTPase activation, ruffles, signal transduction, cytoskeleton
- MeSH terms
- Amino Acid Sequence, Animals, Enzyme Activation, Fluorescent Antibody Technique, Guanine Nucleotides, Humans, Microtubule-Associated Proteins, Molecular Sequence Data, Proteins, Proto-Oncogene Proteins, Recombinant Proteins, Gene Library, Open Reading Frames, 3T3 Cells, Sequence Homology, Amino Acid, GTP-Binding Proteins, COS Cells, GTP Phosphohydrolases, Guanine Nucleotide Exchange Factors, ras Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, ras GTPase-Activating Proteins, rho GTP-Binding Proteins, rac GTP-Binding Proteins, Mice, Rho Guanine Nucleotide Exchange Factors
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