IkappaBalpha and IkappaBalpha /NF-kappa B complexes are retained in the cytoplasm through interaction with a novel partner, RasGAP SH3-binding protein 2.
IkappaBalpha inhibits the transcriptional activity of NF-kappaB both in the cytoplasm by preventing the nuclear translocation of NF-kappaB and in the nucleus where it dissociates NF-kappaB from DNA and transports it back to the cytoplasm. Cytoplasmic localization of inactive NF-kappaB/IkappaBalpha complexes is controlled by mutual masking of nuclear import sequences ... of NF-kappaB p65 and IkappaBalpha and active CRM1-mediated nuclear export. Here, we describe an additional mechanism accounting for the cytoplasmic anchoring of IkappaBalpha or NF-kappaB/IkappaBalpha complexes. The N-terminal domain of IkappaBalpha contains a sequence responsible for the cytoplasmic retention of IkappaBalpha that is specifically recognized by G3BP2, a cytoplasmic protein that interacts with both IkappaBalpha and IkappaBalpha/NF-kappaB complexes. G3BP2 is composed of an N-terminal domain homologous to the NTF2 protein, followed by an acidic domain sufficient for the interaction with the IkappaBalpha cytoplasmic retention sequence, a region containing five PXXP motifs and a C-terminal domain containing RNA-binding motifs. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm, indicating that subcellular distribution of IkappaBalpha and NF-kappaB/IkappaBalpha complexes likely results from a equilibrium between nuclear import, nuclear export, and cytoplasmic retention. The molecular organization of G3BP2 suggests that this putative scaffold protein might connect the NF-kappaB signal transduction cascade with cellular functions such as nuclear transport or RNA metabolism.
Mesh Terms:
Binding Sites, Carrier Proteins, Cytoplasm, DNA-Binding Proteins, Fluorescent Antibody Technique, Genes, Reporter, Hela Cells, Humans, I-kappa B Proteins, Macromolecular Substances, Mutation, NF-kappa B, Nuclear Localization Signals, Precipitin Tests, Protein Binding, Protein Sorting Signals, Protein Structure, Tertiary, Protein Transport, Pyruvate Kinase, Receptors, Glucocorticoid, Recombinant Fusion Proteins, Repressor Proteins, Transfection
Binding Sites, Carrier Proteins, Cytoplasm, DNA-Binding Proteins, Fluorescent Antibody Technique, Genes, Reporter, Hela Cells, Humans, I-kappa B Proteins, Macromolecular Substances, Mutation, NF-kappa B, Nuclear Localization Signals, Precipitin Tests, Protein Binding, Protein Sorting Signals, Protein Structure, Tertiary, Protein Transport, Pyruvate Kinase, Receptors, Glucocorticoid, Recombinant Fusion Proteins, Repressor Proteins, Transfection
J. Biol. Chem.
Date: Nov. 17, 2000
PubMed ID: 10969074
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