Signal transduction mechanisms of CD137 ligand in human monocytes

Cell Signal. 2007 Sep;19(9):1899-908. doi: 10.1016/j.cellsig.2007.04.014.


Bidirectional signalling, i.e. simultaneous signalling through a receptor as well as its cell surface-bound ligand has been identified for several members of the TNF and TNF receptor family members. Reverse signalling through the ligands offers the advantage of an immediate feed-back and a more precise fine tuning of biological responses. Little is known about the molecular nature of reverse signalling through the ligands. CD137 ligand, member of the TNF family is expressed on monocytes and induces activation, migration, prolongation of survival and proliferation of monocytes. Here we show that reverse signalling by CD137 ligand is mediated by protein tyrosine kinases, p38 mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1,2, MAP/ERK kinase (MEK), Phosphoinositide-3-kinase (PI3-K) and protein kinase A (PKA) but not by protein kinase C (PKC). This study also shows that reverse signalling relies on the same signal transduction molecules as signalling through classical receptors and is in its nature not different from it.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand / metabolism*
  • Alkaloids / pharmacology
  • Androstadienes / pharmacology
  • Benzophenanthridines / pharmacology
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Interleukin-8 / metabolism
  • MAP Kinase Signaling System / drug effects
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / enzymology
  • Monocytes / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Phosphotyrosine / metabolism
  • Protein Kinase C / metabolism
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction* / drug effects
  • Thionucleotides / pharmacology
  • Wortmannin


  • 4-1BB Ligand
  • 4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine
  • Alkaloids
  • Androstadienes
  • Benzophenanthridines
  • Interleukin-8
  • Pyrazoles
  • Pyrimidines
  • Thionucleotides
  • Phosphotyrosine
  • adenosine-3',5'-cyclic phosphorothioate
  • Cyclic AMP
  • chelerythrine
  • Phosphatidylinositol 3-Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Wortmannin