Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Amino Acid Sequence
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Animals
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CD40 Ligand / metabolism*
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CSK Tyrosine-Protein Kinase
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Carrier Proteins / metabolism*
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Cell Line
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Cell Survival
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Cells, Cultured
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Dendritic Cells / metabolism
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Enzyme Activation
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Humans
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Kinetics
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Ligands
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Membrane Glycoproteins / metabolism*
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Mice
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Models, Biological
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Molecular Sequence Data
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Osteoclasts / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / metabolism*
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Phosphorylation
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Plasmids / metabolism
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Precipitin Tests
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Protein Binding
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Protein Serine-Threonine Kinases*
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-cbl
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Sequence Homology, Amino Acid
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Signal Transduction
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Transfection
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Ubiquitin-Protein Ligases*
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src-Family Kinases
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cblb protein, mouse
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Ligands
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Membrane Glycoproteins
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Phosphoproteins
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Proto-Oncogene Proteins
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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TNFRSF11A protein, human
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TNFSF11 protein, human
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Tnfrsf11a protein, mouse
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Tnfsf11 protein, mouse
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CD40 Ligand
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CBLB protein, human
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Protein-Tyrosine Kinases
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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CBL protein, human
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Cbl protein, mouse