IκB kinase γ/nuclear factor-κB-essential modulator (IKKγ/NEMO) facilitates RhoA GTPase activation, which, in turn, activates Rho-associated KINASE (ROCK) to phosphorylate IKKβ in response to transforming growth factor (TGF)-β1.
Transforming growth factor (TGF)-β1 plays several roles in a variety of cellular functions. TGF-β1 transmits its signal through Smad transcription factor-dependent and -independent pathways. It was reported that TGF-β1 activates NF-κB and RhoA, and RhoA activates NF-κB in several kinds of cells in a Smad-independent pathway. However, the activation molecular ... mechanism of NF-κB by RhoA upon TGF-β1 has not been clearly elucidated. We observed that RhoA-GTP level was increased by TGF-β1 in RAW264.7 cells. RhoA-GDP and RhoGDI were bound to N- and C-terminal domains of IKKγ, respectively. Purified IKKγ facilitated GTP binding to RhoA complexed with RhoGDI. Furthermore, Dbs, a guanine nucletotide exchange factor of RhoA much more enhanced GTP binding to RhoA complexed with RhoGDI in the presence of IKKγ. Indeed, si-IKKγ abolished RhoA activation in response to TGF-β1 in cells. However, TGF-β1 stimulated the release of RhoA-GTP from IKKγ and Rho-associated kinase (ROCK), an active RhoA effector protein, directly phosphorylated IKKβ in vitro, whereas TGF-β1-activated kinase 1 activated RhoA upon TGF-β1 stimulation. Taken together, our data indicate that IKKγ facilitates RhoA activation via a guanine nucletotide exchange factor, which in turn activates ROCK to phosphorylate IKKβ, leading to NF-κB activation that induced the chemokine expression and cell migration upon TGF-β1.
Mesh Terms:
Animals, Cell Line, Cell Movement, Chemokines, Enzyme Activation, Gene Expression Regulation, Humans, I-kappa B Kinase, Intracellular Signaling Peptides and Proteins, Mice, NF-kappa B, Phosphorylation, Protein Structure, Tertiary, Transforming Growth Factor beta1, rho GTP-Binding Proteins, rho Guanine Nucleotide Dissociation Inhibitor alpha, rho-Associated Kinases, rhoA GTP-Binding Protein
Animals, Cell Line, Cell Movement, Chemokines, Enzyme Activation, Gene Expression Regulation, Humans, I-kappa B Kinase, Intracellular Signaling Peptides and Proteins, Mice, NF-kappa B, Phosphorylation, Protein Structure, Tertiary, Transforming Growth Factor beta1, rho GTP-Binding Proteins, rho Guanine Nucleotide Dissociation Inhibitor alpha, rho-Associated Kinases, rhoA GTP-Binding Protein
J. Biol. Chem.
Date: Jan. 17, 2014
PubMed ID: 24240172
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