Relaxin activates the MAP kinase pathway in human endometrial stromal cells

J Cell Biochem. 2002;85(3):536-44. doi: 10.1002/jcb.10150.


The reproductive hormone, relaxin, is structurally similar to insulin and insulin-like growth factor (IGF). Although a number of cellular responses to relaxin have been described, intracellular signaling mechanisms that link relaxin receptor engagement to alterations in gene expression remain uncharacterized. In the present study, relaxin treatment of a well-characterized target, human endometrial stromal cells, resulted in rapid activation of p42/44 mitogen-activated protein (MAP) kinase, as well as of MAPK (or ERK) kinase (MEK). Using a selective chemical inhibitor of MEK, it was further demonstrated that MEK phosphorylation is critical for relaxin-induced MAP kinase activation. Relaxin treatment also induced MAP kinase activation in THP-1 monocytic cells and in human smooth muscle cells, indicating that it may be a major signaling transducer utilized by the relaxin receptor. In contrast to insulin or IGF-1, relaxin did not trigger the PI 3-kinase/Akt pathway, perhaps accounting in part for relaxin's unique biological profile. Relaxin was also found to cause activation of the transcription factor CREB, a substrate of the MAP kinase pathway. Finally, activation of the MAP kinase pathway was shown to be essential for optimal stimulation of expression of the gene for vascular endothelial growth factor.

MeSH terms

  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Endometrium / cytology
  • Endometrium / metabolism*
  • Endothelial Growth Factors / genetics
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • JNK Mitogen-Activated Protein Kinases
  • Leukemia / metabolism
  • Lymphokines / drug effects
  • Lymphokines / genetics
  • MAP Kinase Kinase Kinase 1*
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism*
  • Monocytes / metabolism
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Recombinant Proteins / pharmacology
  • Relaxin / metabolism*
  • Relaxin / pharmacology
  • Stromal Cells / metabolism*
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Cyclic AMP Response Element-Binding Protein
  • Endothelial Growth Factors
  • Enzyme Inhibitors
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Relaxin
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human