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Ras-dependent and -independent pathways target the mitogen-activated protein kinase network in macrophages

D Büscher1, R A Hipskind, S Krautwald

  • 1Department of Immunobiology, Fraunhofer Institute for Toxicology and Molecular Biology, Hannover Medical School, Germany.

Molecular and Cellular Biology
|January 1, 1995
PubMed

Insights

Colony-stimulating factor 1 (CSF-1) and bacterial lipopolysaccharide (LPS) activate mitogen-activated protein kinases (MAPKs) via distinct pathways in macrophages. CSF-1 uses a Ras-dependent pathway, while LPS utilizes protein kinase C.

Area of Science:

  • Cellular signaling pathways
  • Signal transduction in macrophages
  • Mitogen-activated protein kinase (MAPK) network

Background:

  • Macrophages respond to various extracellular stimuli like CSF-1 and LPS.
  • CSF-1 promotes proliferation, whereas LPS induces growth inhibition, differentiation, and activation.
  • Both stimuli rapidly activate the MAPK network, phosphorylating ternary complex factors (TCFs).

Purpose of the Study:

  • To elucidate the distinct molecular mechanisms by which CSF-1 and LPS activate the MAPK network in macrophages.
  • To identify the specific signaling components downstream of CSF-1 and LPS that mediate MAPK activation.
  • To differentiate between Ras-dependent and Ras-independent pathways in MAPK activation.

Main Methods:

  • Investigated the formation of p21ras.GTP complexes following CSF-1 and LPS stimulation.
  • Utilized dominant-negative Ras mutants to assess Ras dependency in CSF-1 signaling.
  • Employed phosphatidylcholine-specific phospholipase C inhibitor (D609) and protein kinase C inhibition to study LPS signaling.
  • Examined the phosphorylation of TCF/Elk and TCF/SAP under various inhibitory conditions.

Main Results:

  • CSF-1 stimulated Ras.GTP complex formation, and dominant-negative Ras partially inhibited CSF-1-mediated MEK/MAPK activation.
  • LPS-mediated activation of Raf-1, MEK, and MAPK was suppressed by D609 and protein kinase C inhibition.
  • Activated Raf-1 alone was insufficient for MEK/MAPK activation.
  • TCF/Elk phosphorylation was MAPK-dependent, while TCF/SAP phosphorylation occurred via a MAPK-independent pathway.

Conclusions:

  • CSF-1 and LPS activate the MAPK network through alternative pathways, both converging on Raf-1 activation.
  • The mitogenic pathway stimulated by CSF-1 is Ras-dependent.
  • The differentiation/activation pathway induced by LPS relies on protein kinase C and phosphatidylcholine-specific phospholipase C activation.
  • TCF/SAP phosphorylation represents a distinct signaling event independent of the canonical MAPK cascade.

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