A positive regulatory role for Cbl family proteins in tumor necrosis factor-related activation-induced cytokine (trance) and CD40L-mediated Akt activation.
Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) is a TNF family member essential for osteoclast differentiation, and it induces the activation and survival of osteoclasts and mature dendritic cells. We recently demonstrated that TRANCE activates Akt via a mechanism involving TRANCE receptor (TRANCE-R)/RANK, TRAF6, and c-Src. Here, we show that ... TRANCE-R and CD40 recruit TRAF6, Cbl family-scaffolding proteins, and the phospholipid kinase phosphatidylinositol 3-kinase in a ligand-dependent manner. The recruitment of Cbl-b and c-Cbl to TRANCE-R is dependent upon the activity of Src-family kinases. TRANCE and CD40L-mediated Akt activation is defective in Cbl-b -/- dendritic cells, and CD40L-mediated Akt activation is defective in c-Cbl -/- B cells. These findings implicate Cbl family proteins as not only negative regulators of signaling but as positive modulators of TNF receptor superfamily signaling as well.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, CD40 Ligand, Carrier Proteins, Cell Line, Cell Survival, Cells, Cultured, Dendritic Cells, Enzyme Activation, Humans, Kinetics, Ligands, Membrane Glycoproteins, Mice, Models, Biological, Molecular Sequence Data, Osteoclasts, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-cbl, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Sequence Homology, Amino Acid, Signal Transduction, Transfection, Ubiquitin-Protein Ligases
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, CD40 Ligand, Carrier Proteins, Cell Line, Cell Survival, Cells, Cultured, Dendritic Cells, Enzyme Activation, Humans, Kinetics, Ligands, Membrane Glycoproteins, Mice, Models, Biological, Molecular Sequence Data, Osteoclasts, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-cbl, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Sequence Homology, Amino Acid, Signal Transduction, Transfection, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: Aug. 10, 2001
PubMed ID: 11406619
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