Proteopedia

Rho guanine nucleotide exchange factor

Function

Rho guanine nucleotide exchange factor (GEF) stimulate the exchange of the inactive GDP-bound GTPase to its active GTP-bound form. Binding of GEF to GDP-GTPase catalyzes the dissociation of GDP from the protein[1]. GEF domains include the catalytic DH/PH (Dbl Homology/Pleckstrin Homology) domain; the CH (Calponin Homology) domain is believed to be involved in calcium regulation; the SH3 domain interacts with proline-rich sequences.

  • Rho guanine nucleotide exchange factor 1 binds to G proteins and stimulate Rho-dependent signals.
  • Rho guanine nucleotide exchange factor 3 acts on RHOA and RHOB involved in bone biology.
  • Rho guanine nucleotide exchange factor 6 and Rho guanine nucleotide exchange factor 7 act on Rac1.
  • Rho guanine nucleotide exchange factor 9 mutations involved in developmental and epileptic encephalopathy[2].
  • Rho guanine nucleotide exchange factor 11 mediates Rho-myosin light chain signaling pathways at cell-cell junctions[3].
  • Rho guanine nucleotide exchange factor 18 regulates tissue architecture and function via RhoA activation[4].
  • Rho guanine nucleotide exchange factor 25 involved in contraction of vascular smooth muscle.

Disease

Increased GEF activity is involved in cancer cell proliferation by affecting Rho GTPases [5].

3D Structures of Rho guanine nucleotide exchange factor

Rho guanine nucleotide exchange factor 3D structures


Human Rho guanine nucleotide exchange factor 11 DH/PH domain (grey) complex with transforming protein RhoA (cyan), GSP and Mg+2 ion (green) (PDB code 3kz1)

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Cherfils J, Zeghouf M. Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev. 2013 Jan;93(1):269-309. doi: 10.1152/physrev.00003.2012. PMID:23303910 doi:http://dx.doi.org/10.1152/physrev.00003.2012
  2. ↑ Yang H, Liao H, Gan S, Xiao T, Wu L. ARHGEF9 gene variant leads to developmental and epileptic encephalopathy: Genotypic phenotype analysis and treatment exploration. Mol Genet Genomic Med. 2022 Jul;10(7):e1967. PMID:35638461 doi:10.1002/mgg3.1967
  3. ↑ Itoh M, Tsukita S, Yamazaki Y, Sugimoto H. Rho GTP exchange factor ARHGEF11 regulates the integrity of epithelial junctions by connecting ZO-1 and RhoA-myosin II signaling. Proc Natl Acad Sci U S A. 2012 Jun 19;109(25):9905-10. PMID:22665792 doi:10.1073/pnas.1115063109
  4. ↑ Herder C, Swiercz JM, Müller C, Peravali R, Quiring R, Offermanns S, Wittbrodt J, Loosli F. ArhGEF18 regulates RhoA-Rock2 signaling to maintain neuro-epithelial apico-basal polarity and proliferation. Development. 2013 Jul;140(13):2787-97. PMID:23698346 doi:10.1242/dev.096487
  5. ↑ Cook DR, Rossman KL, Der CJ. Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease. Oncogene. 2014 Jul 31;33(31):4021-35. doi: 10.1038/onc.2013.362. Epub 2013 Sep, 16. PMID:24037532 doi:http://dx.doi.org/10.1038/onc.2013.362

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Michal Harel, Joel L. Sussman
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