title: Identification of a negative regulatory region for the exchange activity and characterization of T332I mutant of Rho guanine nucleotide exchange factor 10 (ARHGEF10).
abstract: The T332I mutation in Rho guanine nucleotide exchange factor 10 (ARHGEF10) was previously found in persons with slowed nerve conduction velocities and thin myelination of peripheral nerves. However, the molecular and cellular basis of the T332I mutant is not understood. Here, we show that ARHGEF10 has a negative regulatory region in the N terminus, in which residue 332 is located, and the T332I mutant is constitutively active. An N-terminal truncated ARHGEF10 mutant, ARHGEF10 ΔN (lacking amino acids 1-332), induced cell contraction that was inhibited by a Rho kinase inhibitor Y27632 and had higher GEF activity for RhoA than the wild type. The T332I mutant also showed the phenotype similar to the N-terminal truncated mutant. These data suggest that the ARHGEF10 T332I mutation-associated phenotype observed in the peripheral nerves is due to activated GEF activity of the ARHGEF10 T332I mutant.
authors: Division of Health Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors: Taro
authors: T
authors: Chaya
authors: Satoshi
authors: S
authors: Shibata
authors: Yasunori
authors: Y
authors: Tokuhara
authors: Wataru
authors: W
authors: Yamaguchi
authors: Hiroshi
authors: H
authors: Matsumoto
authors: Ichiro
authors: I
authors: Kawahara
authors: Mikihiko
authors: M
authors: Kogo
authors: Yoshiharu
authors: Y
authors: Ohoka
authors: Shinobu
authors: S
authors: Inagaki
mesh_terms: D000577:Amides / Q000494:pharmacology; D019943:Amino Acid Substitution; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D010449:Peptide Mapping / Q000379:methods; D010525:Peripheral Nerves / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D064067:Rho Guanine Nucleotide Exchange Factors; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C577232:ARHGEF10 protein, human; D000577:Amides; D004791:Enzyme Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D011725:Pyridines; D064067:Rho Guanine Nucleotide Exchange Factors; C066737:RHOA protein, human; C108830:Y 27632; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein