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.
Arron
J R
JR
Laboratory of Immunology and Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021, USA.
Vologodskaia
M
M
Wong
B R
BR
Naramura
M
M
Kim
N
N
Gu
H
H
Choi
Y
Y
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D023201:CD40 Ligand / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D050721:Proto-Oncogene Proteins c-cbl; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D019061:src-Family Kinases
D048868:Adaptor Proteins, Signal Transducing; D023201:CD40 Ligand; D000081247:CSK Tyrosine-Protein Kinase; D002352:Carrier Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050721:Proto-Oncogene Proteins c-cbl; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D044767:Ubiquitin-Protein Ligases; D019061:src-Family Kinases; C118387:Cblb protein, mouse; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C492211:CBLB protein, human; C000631346:CSK protein, human; C494918:AKT1 protein, human; C067419:CBL protein, human; C493849:Cbl protein, mouse