Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease
Open accessAbstract
The aberrant activity of Ras homologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, in contrast to the direct mutational activation of Ras found in cancer and developmental disorders, Rho GTPases are activated most commonly in disease by indirect mechanisms. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). RhoGEFs promote formation of the active GTP-bound state of Rho GTPases. The largest family of RhoGEFs is comprised of the Dbl family RhoGEFs with 70 human members. The multitude of RhoGEFs that activate a single Rho GTPase reflects the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. In this review, we summarize the role of Dbl RhoGEFs in development and disease, with a focus on Ect2 (epithelial cell transforming squence 2), Tiam1 (T-cell lymphoma invasion and metastasis 1), Vav and P-Rex1/2 (PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-triphosphate)-dependent Rac exchanger).
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DH GEFs constitute the larger of the two classes, with over 70 members.
“DH GEFs constitute the larger of the two classes, with over 70 members (30, 31).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [30]
In “The discovery of RhoGEFs: diverse in numbers and structure” (page not supplied), the paper reports 70 human Dbl-family RhoGEFs and 11 human DOCK-family RhoGEFs. This supports that the DH/Dbl class is larger, but not the claim that it has over 70 members. (LLM, conf=0.90)
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Self-citationRHOA takes the RHOad less traveled to cancer
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Self-citationBarrio‐Real, L., Benedetti, L. G., Engel, N., Tu, Y., Cho, S., Sukumar, S. V., & Kazanietz, M. G. (2014) · Breast Cancer Research · doi:10.1186/s13058-014-0441-7 · Cited by 41 · see citing works
Hsc70 chaperone activity underlies Trio GEF function in axon growth and guidance induced by netrin-1
DeGeer, J., Kaplan, A., Mattar, P. A., Morabito, M., Stochaj, U., Kennedy, T. E., Debant, A., Cayouette, M., Fournier, A. E., & Lamarche‐Vane, N. (2015) · The Journal of Cell Biology · doi:10.1083/jcb.201505084 · Cited by 41 · see citing works
Veluthakal, R., Tunduguru, R., Arora, D. K., Sidarala, V., Syeda, K., Vlaar, C. P., Thurmond, D. C., & Kowluru, A. (2015) · Diabetologia · doi:10.1007/s00125-015-3707-4 · Cited by 41 · see citing works
Namekata, K., Guo, X., Kimura, A., Arai, N., Harada, C., & Harada, T. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007645 · Cited by 40 · see citing works
BAR domain proteins regulate Rho GTPase signaling
Aspenström, P. (2014) · Small GTPases · doi:10.4161/sgtp.28580 · Cited by 40 · see citing works
Apical polarity proteins recruit the RhoGEF Cysts to promote junctional myosin assembly
Silver, J. T., Wirtz-Peitz, F., Simões, S., Pellikka, M., Yan, D., Binari, R., Nishimura, T., Li, Y., Harris, T., Perrimon, N., et al. (2019) · Journal of Cell Biology · doi:10.1083/jcb.201807106 · Cited by 32 · see citing works
Rac Attack: Modulation of the Small GTPase Rac in Inflammatory Bowel Disease and Thiopurine Therapy
Seinen, M. L., Amerongen, G. P. V. N., de Boer, N. K. H., & Bodegraven, A. A. V. (2016) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-016-0232-1 · Cited by 39 · see citing works
Botwright, N. A., Mohamed, A. R., Slinger, J., Lima, P. C., & Wynne, J. W. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.672700 · Cited by 39 · see citing works
Filling GAPs in our knowledge: ARHGAP11A and RACGAP1 act as oncogenes in basal-like breast cancers
Lawson, C. D., & Der, C. J. (2016) · Small GTPases · doi:10.1080/21541248.2016.1220350 · Cited by 39 · see citing works
Self-citationGaitanos, T. N., Koerner, J., & Klein, R. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201512010 · Cited by 37 · see citing works
Cooke, M., Kreider-Letterman, G., Baker, M. J., Zhang, S., Sullivan, N. T., Eruslanov, E. B., Abba, M. C., Goicoechea, S. M., García‐Mata, R., & Kazanietz, M. G. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109905 · Cited by 37 · see citing works
Vargas, P. P., Cooper, S., Sero, J., Bousgouni, V., Arias-García, M., & Bakal, C. (2017) · Scientific Data · doi:10.1038/sdata.2017.18 · Cited by 38 · see citing works
Small-Molecule Protein-Protein Interaction Inhibitor of Oncogenic Rho Signaling
Diviani, D., Raimondi, F., del Vescovo, C. D., Dreyer, E., Reggi, E., Osman, H., Ruggieri, L., Gonano, C., Cavin, S., Box, C. L., et al. (2016) · Cell chemical biology · doi:10.1016/j.chembiol.2016.07.015 · Cited by 37 · see citing works
Lu, S., Hernan, R., Marcogliese, P. C., Huang, Y., Gertler, T. S., Akçaboy, M., Liu, S., Chung, H.-L., Pan, X., Sun, X., et al. (2022) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2022.01.020 · Cited by 37 · see citing works
Vázquez‐Prado, J., Bracho‐Valdés, I., Cervantes‐Villagrana, R. D., & Reyes‐Cruz, G. (2016) · Molecular Pharmacology · doi:10.1124/mol.116.105338 · Cited by 36 · see citing works
Rho GTPases and the emerging role of tunneling nanotubes in physiology and disease
Zhang, S., Kazanietz, M. G., & Cooke, M. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00351.2020 · Cited by 36 · see citing works
Zhang, X., Ren, L., Wu, J., Feng, R., Chen, Y., Li, R., Wu, M., Zheng, M., Wu, X. G., Luo, W., et al. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02441-y · Cited by 37 · see citing works
ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma
Ryan, M. B., Finn, A. J., Pedone, K. H., Thomas, N. E., Der, C. J., & Cox, A. D. (2016) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-16-0184 · Cited by 36 · see citing works
Self-citationTay, Y. D., Leda, M., Goryachev, A. B., & Sawin, K. E. (2018) · Journal of Cell Science · doi:10.1242/jcs.216580 · Cited by 35 · see citing works
- Authors
- Cook, D. R., Rossman, K. L., & Der, C. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Der, C J
- ORCID
- Venue
- Oncogene
- Published
- 2013-09-16
- Volume
- 33
- Issue
- 31
- Pages
- 4021-4035
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC4875565
- OpenAlex
- W2024222958
- Cited by
- 378
- References
- 230
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 17 · 2023: 26 · 2022: 35 · 2021: 45 · 2020: 43 · 2019: 33 · 2018: 37 · 2017: 29 · 2016: 34 · 2015: 24 · 2014: 23 · 2013: 3
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Pancreatic Cancer Action Network
- National Institutes of Health (5r01ca042978-30)
- National Cancer Institute (CA159821, CA 71341, R01-CA042978, F31CA159821, T32CA071341)
- 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 › Hippo pathway signaling and YAP/TAZ
- Keywords
- RhoGEF, Rho GTPases, ECT2, Tiam1, Vav, Rho activation, cancer, developmental disorders, phosphatidylinositol 3,4,5-trisphosphate, small GTPase signaling
- MeSH terms
- Congenital Abnormalities, Animals, Cell Division, Humans, Neoplasms, Gene Expression Regulation, Neoplastic, rho GTP-Binding Proteins, Genetic Diseases, Inborn, Proto-Oncogene Proteins c-vav, Rho Guanine Nucleotide Exchange Factors
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