The annexin protein lipocortin 1 regulates the MAPK/ERK pathway.
Lipocortin 1 (annexin 1) is a calcium- and phospholipid-binding protein that modulates anti-inflammatory responses including those induced by lipopolysaccharide. To investigate the precise role of lipocortin 1 in regulating the lipopolysaccharide-induced signal transduction pathways, we generated stable RAW 264.7 macrophage cell lines expressing decreased and increased lipocortin 1 protein. Several RAW 264.7 clones with increased lipocortin 1 protein levels showed constitutive activation of the mitogen-activated protein kinase extracellular signal-regulated kinase, which was down-regulated following lipopolysaccharide treatment. Conversely, clones with decreased lipocortin 1 protein expression showed prolonged extracellular signal-regulated kinase activity, following lipopolysaccharide activation. Lipocortin 1 specifically regulates the components of the extracellular signal-regulated kinase pathway, since changes in lipocortin 1 protein expression had no affect on the related mitogen-activated protein kinases p38 and c-Jun N-terminal kinase. Lipocortin 1 modulated upstream components of the extracellular signal-regulated kinase pathway and associated with the adaptor protein growth factor binding protein. The downstream consequences of altered extracellular signal-regulated kinase activity were independent of the proinflammatory transcription factor nuclear factor kappa B. These data indicate that lipocortin 1 specifically regulates proximal signaling components of the extracellular signal-regulated kinase signal transduction pathway, resulting in the modulation of biochemical functions in RAW macrophages.
Alldridge
L C
LC
Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 OES, United Kingdom.
Harris
H J
HJ
Plevin
R
R
Hannon
R
R
Bryant
C E
CE
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017305:Annexin A1 / Q000378:metabolism*; D001483:Base Sequence; D001692:Biological Transport; D002460:Cell Line; D017931:DNA Primers; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017305:Annexin A1; D017931:DNA Primers; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011506:Proteins; D020928:Mitogen-Activated Protein Kinases