Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CSK Tyrosine-Protein Kinase
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Carrier Proteins / physiology*
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Cells, Cultured
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Dendritic Cells / physiology
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Membrane Glycoproteins / physiology*
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Osteoclasts / physiology*
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Protein Serine-Threonine Kinases / physiology*
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Protein-Tyrosine Kinases / physiology*
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Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins*
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RANK Ligand
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Receptors, Tumor Necrosis Factor / physiology
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Signal Transduction*
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TNF Receptor-Associated Factor 6
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Tumor Necrosis Factor-alpha / physiology
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src-Family Kinases
Substances
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Carrier Proteins
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Membrane Glycoproteins
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Proteins
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Proto-Oncogene Proteins
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RANK Ligand
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Receptors, Tumor Necrosis Factor
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TNF Receptor-Associated Factor 6
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Tumor Necrosis Factor-alpha
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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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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt