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J Biol Chem, Vol. 274, Issue 53, 37620-37628, December 31, 1999

The Annexin Protein Lipocortin 1 Regulates the MAPK/ERK Pathway^*

Louise C. Alldridge^§, Hayley J. Harris^§, Robin Plevin^¶, Robert Hannon, and Clare E. Bryant^§**

From the  Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 OES, United Kingdom, the ^¶ Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland, and the  Department of Biochemical Pharmacology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom

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.

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^* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^§ Supported by a Wellcome Research Career Development Fellowship award (to C. E. B.).

^** To whom correspondence should be addressed. Fax: 44-1223-337610; E-mail: ceb27@cus.cam.ac.uk.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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