Alternative titles; symbols
HGNC Approved Gene Symbol: ANXA1
Cytogenetic location: 9q21.13 Genomic coordinates (GRCh38): 9:73,151,865-73,170,393 (from NCBI)
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.
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.
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.
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.
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.
Using mice in 3 distinct models of T cell-mediated inflammation, Yang et al. (2013) showed that AnxA1 deficiency significantly increased antigen-induced T cell proliferation and the resulting inflammation. In a contact hypersensitivity model, there was increased adhesion of T cells, including those expressing Ror-gamma-t (RORC; 602943) and IL17a (603149), and neutrophils in the dermal microvasculature. In collagen-induced arthritis, susceptibility was increased as was antigen-specific T cell activation. In delayed hypersensitivity, there was increased release of IL17 and Ifng (147570). Transfer of AnxA1 -/- T cells to wildtype mice resulted in increased inflammatory responses. Yang et al. (2013) concluded that T cell-expressed AnxA1 attenuates T cell-driven inflammatory responses via effects on intracellular signaling, proliferation, and Th1/Th17 cytokine release.
Crompton, M. R., Moss, S. E., Crumpton, M. J. Diversity in the lipocortin/calpactin family. Cell 55: 1-3, 1988. [PubMed: 2971450] [Full Text: https://doi.org/10.1016/0092-8674(88)90002-5]
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: 1676980] [Full Text: https://doi.org/10.1016/0888-7543(91)90321-5]
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.
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: 2969496]
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: 2967291]
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: 15190345] [Full Text: https://doi.org/10.1038/nature02580]
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: 2968983]
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: 12368905] [Full Text: https://doi.org/10.1038/nm786]
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: 2530899] [Full Text: https://doi.org/10.1002/ajmg.1320340205]
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: 2936963] [Full Text: https://doi.org/10.1038/320077a0]
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: 10882119] [Full Text: https://doi.org/10.1016/s1097-2765(00)80323-8]
Yang, Y. H., Song, W., Deane, J. A., Kao, W., Ooi, J. D., Ngo, D., Kitching, A. R., Morand, E. F., Hickey, M. J. Deficiency of annexin A1 in CD4+ T cells exacerbates T cell-dependent inflammation. J. Immun. 190: 997-1007, 2013. [PubMed: 23267026] [Full Text: https://doi.org/10.4049/jimmunol.1202236]