G Protein β γ Subunit-Dependent Rac-Guanine Nucleotide Exchange Activity of Ras-GRF1/CDC25Mm

Ras-GRF1 has been implicated as a Ras-specific guanine nucleotide exchange factor (GEF), which mediates calcium- and muscarinic receptor-triggered signals in the brain. Although a Dbl homology domain known as a motif conserved among GEFs that target Rho family GTP-binding proteins exists in Ras-GRF1...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 96; no. 9; pp. 4826 - 4831
Main Authors Kiyono, Mari, Satoh, Takaya, Kaziro, Yoshito
Format Journal Article
LanguageEnglish
Published National Academy of Sciences of the United States of America 27.04.1999
Subjects
Antibodies
Family members
Gross domestic product
Mathematical functions
Phosphorylation
Physiological regulation
Plasmids
Proteins
Receptors
Starvation
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Summary:Ras-GRF1 has been implicated as a Ras-specific guanine nucleotide exchange factor (GEF), which mediates calcium- and muscarinic receptor-triggered signals in the brain. Although a Dbl homology domain known as a motif conserved among GEFs that target Rho family GTP-binding proteins exists in Ras-GRF1, GEF activity toward Rho family proteins has not been observed. Here we show that Ras-GRF1 exhibits Rac1-specific GEF activity when recovered from cells overexpressing G protein β γ subunits (Gβ γ). Substitution of conserved amino acids within the Dbl homology domain abolished this activity. Activation of the rac pathway in the cell was further evidenced by synergistic activation of the stress kinase JNK1 by Ras-GRF1 and Gβ γ, which is sensitive to inhibitory action of dominant-negative Rac1(17N). In addition, association of Ras-GRF1 with Rac1(17N) was demonstrated by coimmunoprecipitation. Evidence for the involvement of tyrosine kinase(s) in Gβ γ- mediated induction of Rac1-specific GEF activity was provided by the use of specific inhibitors. These results suggest a role of Ras-GRF1 for regulating Rac-dependent as well as Ras-dependent signaling pathways, particularly in the brain functions.
ISSN:0027-8424
1091-6490