*151690	Links
ANNEXIN A1; ANXA1

Alternative titles; symbols

ANNEXIN I; ANX1
LIPOCORTIN I; LPC1
CALPACTIN II

Gene map locus 9q11-q22

TEXT

CLONING

The antiinflammatory action of glucocorticoids has been attributed to the induction of a group of proteins, collectively called lipocortin, that inhibit phospholipase A2. These proteins are thought to control the biosynthesis of potent mediators of inflammation, prostaglandins and leukotrienes, by inhibiting release of their common precursor, arachidonic acid, a process that requires hydrolysis of phospholipids by phospholipase A2. Lipocortin-like proteins have been isolated from monocytes, neutrophils, renal medullary cells, and other cell types. The predominant active form has an apparent relative molecular mass of 40,000. Partially purified lipocortin mimics the effect of steroids and mediates antiinflammatory activity in various in vivo model systems. Using amino acid sequence information from purified rat lipocortin, Wallner et al. (1986) cloned cDNA for human lipocortin and expressed the gene in E. coli. They confirmed that LPC is a potent inhibitor of phospholipase A2. Lipocortin I belongs to the family of annexins, which are structurally related proteins that have a molecular mass of approximately 35,000 to 40,000. They undergo Ca(2+)-dependent binding to phospholipids that are preferentially located on the cytosolic face of the plasma membrane. The individual proteins in this family have been discovered by investigators with various goals in mind and have been given a variety of names (Kaplan et al., 1988).

Horlick et al. (1991) isolated overlapping mouse genomic clones for Lipo1. The gene in the mouse encodes a protein of 346 amino acid residues.

GENE STRUCTURE

Horlick et al. (1991) demonstrated that the mouse Lipo1 gene spans about 17 kb and is divided into 13 exons. Horlick et al. (1991) pointed out a similarity in gene structure between mouse Lipo1 and Lipo2 (151740), suggesting that they have a recent evolutionary ancestor.

GENE FAMILY

Crompton et al. (1988) reviewed the lipocortin/calpactin family of proteins. Pepinsky et al. (1988) described the characteristics of 3 proteins they called lipocortin III, lipocortin V, and lipocortin VI. Lipocortins III and IV are apparently identical. Shohat et al. (1989) advanced the hypothesis that familial Mediterranean fever (FMF; 249100) patients are homozygous for a mutant allele for one of the lipocortin genes.

MAPPING

Huebner et al. (1987, 1988) mapped the ANXA1 gene to 9q11-q22 by chromosomal in situ hybridization and segregation analysis in somatic cell hybrids using a cDNA clone. By analysis of recombinant inbred strains, Horlick et al. (1991) showed that the Lipo1 gene is located on mouse chromosome 19.

GENE FUNCTION

Walther et al. (2000) showed that ANXA1 acts through the formyl peptide receptor (FPR; 136537) on human neutrophils. Peptides derived from the unique N-terminal domain of ANXA1 serve as FPR ligands and trigger different signaling pathways in a dose-dependent manner. Lower peptide concentrations possibly found in inflammatory situations elicit Ca(2+) transients without fully activating the mitogen-activated protein kinase pathway. This causes a specific inhibition of the transendothelial migration of neutrophils and a desensitization of neutrophils toward a chemoattractant challenge. These findings identified ANXA1 peptides as novel, endogenous FPR ligands and established a mechanistic basis of ANXA1-mediated antiinflammatory effects.

Perretti et al. (2002) reported that inhibition of polymorphonuclear neutrophil infiltration by aspirin and dexamethasone is a property shared by aspirin-triggered lipoxins and the glucocorticoid-induced ANXA1-derived peptides that are both generated in vivo and act at the lipoxin A4 receptor (FPRL1; 136538) to halt polymorphonuclear neutrophil diapedesis. These structurally diverse ligands specifically interact directly with recombinant human ALXR demonstrated by specific radioligand binding and function as well as immunoprecipitation of polymorphonuclear neutrophil receptors. In addition, the combination of both aspirin-triggered lipoxins and ANXA1-derived peptides limited polymorphonuclear neutrophil infiltration and reduced production of inflammatory mediators (i.e., prostaglandins and chemokines) in vivo. Perretti et al. (2002) concluded that the results indicated functional redundancies in endogenous lipid and peptide antiinflammatory circuits that are spatially and temporally separate, where both aspirin-triggered lipoxins and specific ANXA1-derived peptides act in concert at ALXR to downregulate polymorphonuclear neutrophil recruitment to inflammatory loci.

Oh et al. (2004) described a hypothesis-driven, systems biology approach to identifying a small subset of proteins induced at the tissue-blood interface that are inherently accessible to antibodies injected intravenously. They used subcellular fractionation, subtractive proteomics, and bioinformatics to identify endothelial cell surface proteins exhibiting restricted tissue distribution and apparent tissue modulation. Expression profiling and gamma-scintigraphic imaging with antibodies established 2 of these proteins, aminopeptidase-P (602443) and annexin A1, as selective in vivo targets for antibodies in lung and solid tumors, respectively. Radioimmunotherapy to annexin A1 destroyed tumors and increased animal survival.

REFERENCES

1. Crompton, M. R.; Moss, S. E.; Crumpton, M. J. :

Diversity in the lipocortin/calpactin family. Cell 55: 1-3, 1988.
PubMed ID : 2971450

2. Horlick, K. R.; Cheng, I. C.; Wong, W. T.; Wakeland, E. K.; Nick, H. S. :

Mouse lipocortin I gene structure and chromosomal assignment: gene duplication and the origins of a gene family. Genomics 10: 365-374, 1991.
PubMed ID : 1676980

3. Huebner, K.; Cannizzaro, L. A.; Croce, C. M.; Frey, A. Z.; Wallner, B. P.; Hecht, B. K.; Hecht, F. :

Chromosome localization of the human genes for lipocortin I and the lipocortin II family. (Abstract) Cytogenet. Cell Genet. 46: 631 only, 1987.

4. Huebner, K.; Cannizzaro, L. A.; Frey, A. Z.; Hecht, B. K.; Hecht, F.; Croce, C. M.; Wallner, B. P. :

Chromosomal localization of the human genes for lipocortin I and lipocortin II. Oncogene Res. 2: 299-310, 1988.
PubMed ID : 2969496

5. Kaplan, R.; Jaye, M.; Burgess, W. H.; Schlaepfer, D. D.; Haigler, H. T. :

Cloning and expression of cDNA for human endonexin II, a Ca(2+) and phospholipid binding protein. J. Biol. Chem. 263: 8037-8043, 1988.
PubMed ID : 2967291

6. Oh, P.; Li, Y.; Yu, J.; Durr, E.; Krasinska, K. M.; Carver, L. A.; Testa, J. E.; Schnitzer, J. E. :

Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy. Nature 429: 629-635, 2004.
PubMed ID : 15190345

7. Pepinsky, R. B.; Tizard, R.; Mattaliano, R. J.; Sinclair, L. K.; Miller, G. T.; Browning, J. L.; Chow, E. P.; Burne, C.; Huang, K.-S.; Pratt, D.; Wachter, L.; Hession, C.; Frey, A. Z.; Wallner, B. P. :

Five distinct calcium and phospholipid binding proteins share homology with lipocortin I. J. Biol. Chem. 263: 10799-10811, 1988.
PubMed ID : 2968983

8. Perretti, M.; Chiang, N.; La, M.; Fierro, I. M.; Marullo, S.; Getting, S. J.; Solito, E.; Serhan, C. N. :

Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A(4) receptor. Nature Med. 8: 1296-1302, 2002.
PubMed ID : 12368905

9. Shohat, M.; Korenberg, J. R.; Schwabe, A. D.; Rotter, J. I. :

Hypothesis: familial Mediterranean fever--a genetic disorder of the lipocortin family? Am. J. Med. Genet. 34: 163-167, 1989.
PubMed ID : 2530899

10. Wallner, B. P.; Mattaliano, R. J.; Hession, C.; Cate, R. L.; Tizard, R.; Sinclair, L. K.; Foeller, C.; Chow, E. P.; Browning, J. L.; Ramachandran, K. L.; Pepinsky, R. B. :

Cloning and expression of human lipocortin, a phospholipase A2 inhibitor with potential anti-inflammatory activity. Nature 320: 77-81, 1986.
PubMed ID : 2936963

11. Walther, A.; Riehemann, K.; Gerke, V. :

A novel ligand of the formyl peptide receptor: annexin I regulates neutrophil extravasation by interacting with the FPR. Molec. Cell 5: 831-840, 2000.
PubMed ID : 10882119

CONTRIBUTORS

Ada Hamosh - updated : 7/26/2004
Ada Hamosh - updated : 11/15/2002
Stylianos E. Antonarakis - updated : 6/21/2000

CREATION DATE

Victor A. McKusick : 6/25/1986

EDIT HISTORY

alopez : 7/26/2004
terry : 7/26/2004
alopez : 11/18/2002
alopez : 11/18/2002
terry : 11/15/2002
mgross : 6/21/2000
mgross : 9/17/1999
terry : 5/3/1999
alopez : 9/23/1998
dkim : 9/11/1998
carol : 3/20/1998
carol : 9/4/1992
supermim : 3/16/1992
carol : 5/22/1991
carol : 3/20/1991
supermim : 3/20/1990
supermim : 2/9/1990

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