D. Buscher et al., RAS-DEPENDENT AND RAS-INDEPENDENT PATHWAYS TARGET THE MITOGEN-ACTIVATED PROTEIN-KINASE NETWORK IN MACROPHAGES, Molecular and cellular biology, 15(1), 1995, pp. 466-475
Mitogen-activated protein kinases (MAPKs) are activated upon a variety
of extracellular stimuli in different cells. In macrophages, colony-s
timulating factor 1 (CSF-1) stimulates proliferation, while bacterial
lipopolysaccharide (LPS) inhibits cell growth and causes differentiati
on and activation. Both CSF-1 and LPS rapidly activate the MAPK networ
k and induce the phosphorylation of two distinct ternary complex facto
rs (TCFs), TCF/Elk and TCF/SAP. CSF-1, but not LPS, stimulated the for
mation of p21(ras). GTP complexes. Expression of a dominant negative r
as 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 phospholi
pase C inhibitor D609 suppressed LPS-mediated, but not CSF-1-mediated,
activation of Raf-1, MEK, and MAPK. Similarly, down-regulation or inh
ibition 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 wa
s blocked by all treatments that interfered with MAPK activation, impl
ying that TCF/SAP was targeted by a MAPK-independent pathway. Therefor
e, CSF-1 and LPS target the MAPK network by two alternative pathways,
both of which induce Raf-1 activation. The mitogenic pathway depends o
n Ras activity, while the differentiation signal relies on protein kin
ase C and phosphatidylcholine-specific phospholipase C activation.