Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway

Oncogene. 2002 Apr 18;21(17):2641-51. doi: 10.1038/sj.onc.1205346.

Abstract

Previous studies have shown that hematopoietic cytokines, including erythropoietin (Epo) and interleukin (IL)-3, activate the Ras GTPase and the downstream Raf/Erk/Elk-1 signaling pathway. Here we report that Epo or IL-3 rapidly and transiently activates Rac, a Rho family GTPase, in hematopoietic cell lines, 32D/EpoR-Wt and UT-7. The cytokine-induced activation of Rac was augmented in a 32D/EpoR-Wt clone that inducibly overexpresses the adaptor protein CrkL or the Ras guanine nucleotide exchange factor C3G, which forms a complex with CrkL. Furthermore, the Rac activation was enhanced or inhibited in cells inducibly expressing an activated Ras mutant, H-Ras61L, or a dominant negative Ras mutant, H-Ras17N, respectively. In addition, the cytokine-induced Rac activation was inhibited by a phosphatidyl-inositol 3'-kinase (PI3K) inhibitor, LY294002, which also inhibited the Erk activation. A dominant negative Rac mutant, Rac17N, also inhibited the cytokine-induced activation of Erk as well as Elk-1. On the other hand, activation of Akt downstream of PI3K was found to play an inhibitory role in cytokine activation of Erk/Elk-1. Together, these results indicate that Rac is activated by Epo or IL-3 at downstream of the Ras/PI3K pathway in parallel with Akt and plays a role in activation of the Erk/Elk-1 signaling pathway in hematopoietic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Bone Marrow Cells / drug effects*
  • Bone Marrow Cells / enzymology
  • Chromones / pharmacology
  • DNA-Binding Proteins*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Erythropoietin / pharmacology*
  • Guanine Nucleotide-Releasing Factor 2 / metabolism
  • Humans
  • Interleukin-3 / pharmacology*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Morpholines / pharmacology
  • Mutagenesis, Site-Directed
  • Nuclear Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Recombinant Proteins
  • Signal Transduction
  • Transcription Factors*
  • ets-Domain Protein Elk-1
  • rac GTP-Binding Proteins / metabolism*
  • ras Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CRKL protein
  • Chromones
  • DNA-Binding Proteins
  • ELK1 protein, human
  • Elk1 protein, mouse
  • Enzyme Inhibitors
  • Guanine Nucleotide-Releasing Factor 2
  • Interleukin-3
  • Morpholines
  • Nuclear Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Erythropoietin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • rac GTP-Binding Proteins
  • ras Proteins