TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src

Mol Cell. 1999 Dec;4(6):1041-9. doi: 10.1016/s1097-2765(00)80232-4.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CSK Tyrosine-Protein Kinase
  • Carrier Proteins / physiology*
  • Cells, Cultured
  • Dendritic Cells / physiology
  • Membrane Glycoproteins / physiology*
  • Osteoclasts / physiology*
  • Protein-Serine-Threonine Kinases / physiology*
  • Protein-Tyrosine Kinases / physiology*
  • Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • RANK Ligand
  • Receptors, Tumor Necrosis Factor / physiology
  • Signal Transduction*
  • TNF Receptor-Associated Factor 6
  • Tumor Necrosis Factor-alpha / physiology
  • src-Family Kinases

Substances

  • Carrier Proteins
  • Membrane Glycoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • RANK Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF Receptor-Associated Factor 6
  • Tumor Necrosis Factor-alpha
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt