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PMID: 7799956 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Molecular and cellular biology ·Vol. 15 ·No. 1 ·1995-01-00 ·Pages 466-75

Büscher D, Hipskind RA, Krautwald S, Reimann T, Baccarini M

Abstract

Mitogen-activated protein kinases (MAPKs) are activated upon a variety of extracellular stimuli in different cells. In macrophages, colony-stimulating factor 1 (CSF-1) stimulates proliferation, while bacterial lipopolysaccharide (LPS) inhibits cell growth and causes differentiation and activation. Both CSF-1 and LPS rapidly activate the MAPK network and induce the phosphorylation of two distinct ternary complex factors (TCFs), TCF/Elk and TCF/SAP. CSF-1, but not LPS, stimulated the formation of p21ras. GTP complexes. Expression of a dominant negative ras mutant reduced, but did not abolish, CSF-1-mediated stimulation of MEK and MAPK. In contrast, activation of the MEK kinase Raf-1 was Ras independent. Treatment with the phosphatidylcholine-specific phospholipase C inhibitor D609 suppressed LPS-mediated, but not CSF-1-mediated, activation of Raf-1, MEK, and MAPK. Similarly, down-regulation or inhibition of protein kinase C blocked MEK and MAPK induction by LPS but not that by CSF-1. Phorbol 12-myristate 13-acetate pretreatment led to the sustained activation of the Raf-1 kinase but not that of MEK and MAPK. Thus, activated Raf-1 alone does not support MEK/MAPK activation in macrophages. Phosphorylation of TCF/Elk but not that of TCF/SAP was blocked by all treatments that interfered with MAPK activation, implying that TCF/SAP was targeted by a MAPK-independent pathway. Therefore, CSF-1 and LPS target the MAPK network by two alternative pathways, both of which induce Raf-1 activation. The mitogenic pathway depends on Ras activity, while the differentiation signal relies on protein kinase C and phosphatidylcholine-specific phospholipase C activation.

MeSH Terms
Amino Acid Sequence Animals Bridged-Ring Compounds/pharmacology Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cells, Cultured DNA-Binding Proteins/metabolism Enzyme Activation Guanosine Triphosphate/metabolism In Vitro Techniques Indoles/pharmacology Lipopolysaccharides/pharmacology MAP Kinase Kinase Kinase 1 Macrophage Colony-Stimulating Factor/pharmacology Macrophages/enzymology Maleimides/pharmacology Mice Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases Molecular Sequence Data Norbornanes Peptides/chemistry Phosphorylation Protein Kinase C/metabolism Protein Serine-Threonine Kinases Protein-Tyrosine Kinases/metabolism Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-raf Proto-Oncogene Proteins p21(ras)/metabolism Signal Transduction Thiocarbamates Thiones/pharmacology Transcription Factors Type C Phospholipases/metabolism ets-Domain Protein Elk-1
Chemicals
Bridged-Ring Compounds DNA-Binding Proteins Indoles Lipopolysaccharides Maleimides Norbornanes Peptides Proto-Oncogene Proteins Thiocarbamates Thiones Transcription Factors ets-Domain Protein Elk-1 p62TCF protein, mouse tricyclodecane-9-yl-xanthogenate Macrophage Colony-Stimulating Factor Guanosine Triphosphate Protein-Tyrosine Kinases Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-raf Protein Kinase C Calcium-Calmodulin-Dependent Protein Kinases Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases MAP Kinase Kinase Kinase 1 MAP3K1 protein, human Map3k1 protein, mouse Type C Phospholipases Proto-Oncogene Proteins p21(ras) bisindolylmaleimide
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Büscher D
Department of Immunobiology, Fraunhofer Institute for Toxicology and Molecular Biology, Hannover Medical School, Germany.
Hipskind R A
Krautwald S
Reimann T
Baccarini M
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.15.1.466
Published
1995-01-00
Pages
466-75
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC231993
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.15.1.466 PMC Full Text View journal details
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