ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide exchange activity toward RhoA.
Rho GTPases play an essential role in the regulation of many cellular processes. Although various guanine nucleotide exchange factors (GEFs) are involved in the activation of Rho GTPases, the precise mechanism regulating such activity remains unclear. We have examined whether ERK1/2 are involved in the phosphorylation of GEF-H1, a GEF toward RhoA, to modulate its activity. Expression of GEF-H1 in HT1080 cells with constitutive ERK1/2 activation induced its phosphorylation at Thr(678), which was totally abolished by treating the cells with PD184352, an ERK pathway inhibitor. Stimulation of HeLa S3 cells with 12-O-tetradecanoyl-phorbol-13-acetate induced the phosphorylation of GEF-H1 in an ERK-dependent manner. ERK1/2-mediated Thr(678)-phosphorylation enhanced the guanine nucleotide exchange activity of GEF-H1 toward RhoA. These results suggest that the ERK pathway, by enhancing the GEF-H1 activity, contributes to the activation of RhoA to regulate the actin assembly, a necessary event for the induction of cellular responses including proliferation and motility.
Fujishiro
Shuh-Hei
SH
Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan.
Tanimura
Susumu
S
Mure
Shogo
S
Kashimoto
Yuji
Y
Watanabe
Kazushi
K
Kohno
Michiaki
M
D045744:Cell Line, Tumor; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006150:Guanine Nucleotides / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D011485:Protein Binding; D064067:Rho Guanine Nucleotide Exchange Factors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
C577356:ARHGEF2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D006150:Guanine Nucleotides; D064067:Rho Guanine Nucleotide Exchange Factors; D010769:Phosphothreonine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020742:rhoA GTP-Binding Protein