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Extracellular ATP stimulates an inhibitory pathway towards growth factor-induced cRaf-1 and MEKK activation in

G Lenz1, D Gonçalves, Z Luo

  • 1Departments of Biofísica and Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Journal of Neurochemistry
|May 22, 2001
PubMed

Insights

Adenosine triphosphate (ATP) surprisingly inhibits c-Raf-1 activation, a key step in cell proliferation signaling, even while enhancing downstream ERK activation in astrocytes. This suggests a novel inhibitory mechanism integrating growth factor and P2Y receptor pathways.

Area of Science:

  • Cellular signaling
  • Neuroscience
  • Molecular biology

Background:

  • Adenosine triphosphate (ATP) acts via P2Y G protein-coupled receptors (GPCRs) as a mitogenic signal.
  • ATP synergistically enhances fibroblast growth factor-2 (FGF-2)-induced astrocyte proliferation.
  • The extracellular-signal regulated protein kinase (ERK) cascade, including c-Raf-1, MEK, and ERK, regulates cellular proliferation.

Purpose of the Study:

  • To investigate the effects of ATP and FGF-2 cotreatment on the ERK cascade components (c-Raf-1, MEK, ERK) in astrocytes.
  • To elucidate the mechanism of ATP's influence on growth factor-induced proliferation signaling.

Main Methods:

  • Primary cultures of rat cortical astrocytes were utilized.
  • Cells were cotreated with ATP and FGF-2.
  • Activation of c-Raf-1, MEK, and ERK was measured.
  • Involvement of cyclic AMP and protein kinase C was assessed.
  • Effects of other growth factors (EGF, PDGF) and GPCR agonists (serotonin) were examined.

Main Results:

  • ATP surprisingly inhibited FGF-2-induced activation of c-Raf-1 in astrocytes.
  • This inhibition of c-Raf-1 did not reduce MEK and ERK activation; instead, cotreatment led to greater initial ERK activation.
  • ATP also inhibited c-Raf-1 activation by epidermal growth factor and platelet-derived growth factor, and MEKK1/MEKK2 activation.
  • Serotonin did not inhibit FGF-2-induced c-Raf-1 activation, indicating specificity of ATP's inhibitory cross-talk.

Conclusions:

  • ATP stimulates an inhibitory activity upstream of MEK activators.
  • This activity specifically inhibits growth factor-induced activation of c-Raf-1 and MEKKs.
  • This mechanism may integrate signaling from receptor tyrosine kinases and P2Y-GPCRs.

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