TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src.
TRANCE, a TNF family member, and its receptor, TRANCE-R, are critical regulators of dendritic cell and osteoclast function. Here, we demonstrate that TRANCE activates the antiapoptotic serine/threonine kinase Akt/PKB through a signaling complex involving c-Src and TRAF6. A deficiency in c-Src or addition of Src family kinase inhibitors blocks TRANCE-mediated PKB activation in osteoclasts. c-Src and TRAF6 interact with each other and with TRANCE-R upon receptor engagement. TRAF6, in turn, enhances the kinase activity of c-Src leading to tyrosine phosphorylation of downstream signaling molecules such as c-Cbl. These results define a mechanism by which TRANCE activates Src family kinases and PKB and provide evidence of cross-talk between TRAF proteins and Src family kinases.
Wong
B R
BR
Laboratory of Immunology, Rockefeller University, New York, New York 10021, USA.
Besser
D
D
Kim
N
N
Arron
J R
JR
Vologodskaia
M
M
Hanafusa
H
H
Choi
Y
Y
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D053245:RANK Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019061:src-Family Kinases
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D053245:RANK Ligand; D018124:Receptors, Tumor Necrosis Factor; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt