ArticleThe Journal of biological chemistry2011
Mechanistic insights into specificity, activity, and regulatory elements of the regulator of G-protein signaling (RGS)-containing Rho-specific guanine nucleotide exchange factors (GEFs) p115, PDZ-RhoGEF (PRG), and leukemia-associated RhoGEF (LARG).
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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46 citing papers in PubMed, 69 citations in OpenAlex.
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- The biochemical mechanism of Rho GTPase membrane binding, activation and retention in activity patterning.The EMBO journal · 2025Article
- RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice.Current research in toxicology · 2025Article
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- CLIC4 Regulates Endothelial Barrier Control by Mediating PAR1 Signaling via RhoA.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
- RhoA Signaling in Neurodegenerative Diseases.Cells · 2022Review
- Regulation of Leukaemia Associated Rho GEF (LARG/ARHGEF12).Small GTPases · 2022Article
- Selectivity Determinants of RHO GTPase Binding to IQGAPs.International journal of molecular sciences · 2021Article
- Review
- GαThe Journal of biological chemistry · 2020Article
- Histamine-induced biphasic activation of RhoA allows for persistent RhoA signaling.PLoS biology · 2020Article
- Multiplexed GTPase and GEF biosensor imaging enables network connectivity analysis.Nature chemical biology · 2020Article
- MicroRNA Regulation of the Small Rho GTPase Regulators-Complexities and Opportunities in Targeting Cancer Metastasis.Cancers · 2020Review
- Optogenetic Control of RhoA to Probe Subcellular Mechanochemical Circuitry.Current protocols in cell biology · 2020Article
- Differential role for PAK1 and PAK4 during the invadopodia lifecycle.Small GTPases · 2019Article
- Loss of ARHGEF1 causes a human primary antibody deficiency.The Journal of clinical investigation · 2019Article
- Direct regulation of p190RhoGEF by activated Rho and Rac GTPases.Journal of structural biology · 2018Article
- RSK2 drives cell motility by serine phosphorylation of LARG and activation of Rho GTPases.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The multimodular guanine nucleotide exchange factors (GEFs) of the Dbl family mostly share a tandem Dbl homology (DH) and pleckstrin homology (PH) domain organization. The function of these and other domains in the DH-mediated regulation of the GDP/GTP exchange reaction of the Rho proteins is the subject of intensive investigations. This comparative study presents detailed kinetic data on specificity, activity, and regulation of the catalytic DH domains of four GEFs, namely p115, p190, PDZ-RhoGEF (PRG), and leukemia-associated RhoGEF (LARG). We demonstrate that (i) these GEFs are specific guanine nucleotide exchange factors for the Rho isoforms (RhoA, RhoB, and RhoC) and inactive toward other members of the Rho family, including Rac1, Cdc42, and TC10. (ii) The DH domain of LARG exhibits the highest catalytic activity reported for a Dbl protein till now with a maximal acceleration of the nucleotide exchange by 10(7)-fold, which is at least as efficient as reported for GEFs specific for Ran or the bacterial toxin SopE. (iii) A novel regulatory region at the N terminus of the DH domain is involved in its association with GDP-bound RhoA monitored by a fluorescently labeled RhoA. (iv) The tandem PH domains of p115 and PRG efficiently contribute to the DH-mediated nucleotide exchange reaction. (v) In contrast to the isolated DH or DH-PH domains, a p115 fragment encompassing both the regulator of G-protein signaling and the DH domains revealed a significantly reduced GEF activity, supporting the proposed models of an intramolecular autoinhibitory mechanism for p115-like RhoGEFs.
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