|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Papers In Press, published online ahead of print October 17, 2005
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109-0642
Corresponding Author: brocko{at}umich.edu
The enzyme 5-lipoxygenase initiates the synthesis of leukotrienes from arachidonic acid. Protein kinase A phosphorylates 5-lipoxygenase on Ser-523 and this reduces its activity. We report here that phosphorylation of Ser-523 also shifts the subcellular distribution of 5-lipoxygenase from the nucleus to the cytoplasm. Phosphorylation and redistribution of 5-lipoxygenase could be produced by overexpression of the protein kinase A catalytic subunit a, by pharmacological activators of protein kinase A, and by prostaglandin E2. Mimicking phosphorylation by replacing Ser-523 with glutamic acid caused cytoplasmic localization; replacement of Ser-523 with alanine prevented phosphorylation and redistribution in response to protein kinase A activation. Since Ser-523 is positioned within the nuclear localization sequence-518 of 5-lipoxygenase, the ability of protein kinase A to phosphorylate and alter the localization of green fluorescent protein fused to the nuclear localization sequence-518 peptide was also tested. Site-directed replacement of Ser-523 with glutamic acid within the peptide impaired nuclear accumulation; overexpression of the protein kinase A catalytic subunit a and pharmacological activation of protein kinase caused phosphorylation of the fusion protein at Ser-523 and the phosphorylated protein was found chiefly in the cytoplasm. Taken together, these results indicate that phosphorylation of Ser523 inhibits the nuclear import function of a nuclear localization sequence, resulting in the accumulation of 5-lipoxygenase enzyme in the cytoplasm. As cytoplasmic localization can be associated with reduced leukotriene synthetic capacity, phosphorylation of Ser-523 serves to inhibit leukotriene production by both impairing catalytic activity and placing the enzyme in a site that is unfavorable for action.
J. Biol. Chem, 10.1074/jbc.M507045200
Submitted on June 28, 2005
Accepted on October 17, 2005
Phosphorylation by protein kinase A inhibits nuclear import of 5-lipoxygenase
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Flamand, M. Luo, M. Peters-Golden, and T. G. Brock Phosphorylation of Serine 271 on 5-Lipoxygenase and Its Role in Nuclear Export J. Biol. Chem., January 2, 2009; 284(1): 306 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. Hoffmann, I. H. Lambert, and S. F. Pedersen Physiology of Cell Volume Regulation in Vertebrates Physiol Rev, January 1, 2009; 89(1): 193 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ye, Y. Lin, J. R. Perez-Polo, B. F. Uretsky, Z. Ye, B. C. Tieu, and Y. Birnbaum Phosphorylation of 5-Lipoxygenase at Ser523 by Protein Kinase A Determines Whether Pioglitazone and Atorvastatin Induce Proinflammatory Leukotriene B4 or Anti-Inflammatory 15-Epi-Lipoxin A4 Production J. Immunol., September 1, 2008; 181(5): 3515 - 3523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Cordray, K. Doyle, K. Edes, P. J. Moos, and F. A. Fitzpatrick Oxidation of 2-Cys-peroxiredoxins by Arachidonic Acid Peroxide Metabolites of Lipoxygenases and Cyclooxygenase-2 J. Biol. Chem., November 9, 2007; 282(45): 32623 - 32629. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rakonjac, L. Fischer, P. Provost, O. Werz, D. Steinhilber, B. Samuelsson, and O. Radmark Coactosin-like protein supports 5-lipoxygenase enzyme activity and up-regulates leukotriene A4 production PNAS, August 29, 2006; 103(35): 13150 - 13155. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |