Annexin A1

Annexin A1
250px PDB rendering based on 1ain.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1AIN, 1BO9, 1QLS
Identifiers
Symbols	ANXA1 ; ANX1; LPC1
External IDs	OMIM: 151690 MGI: 96819 HomoloGene: 563 GeneCards: ANXA1 Gene
Gene ontology Molecular function • single-stranded DNA binding • single-stranded RNA binding • helicase activity • receptor binding • structural molecule activity • calcium ion binding • protein binding • phospholipid binding • calcium-dependent phospholipid binding • phospholipase A2 inhibitor activity • protein binding, bridging • double-stranded DNA-dependent ATPase activity • annealing helicase activity • protein homodimerization activity • calcium-dependent protein binding Cellular component • cornified envelope • extracellular region • extracellular space • nucleus • cytoplasm • endosome • plasma membrane • focal adhesion • cilium • cell surface • basolateral plasma membrane • mitochondrial membrane • vesicle • sarcolemma • mast cell granule • protein complex • extracellular exosome Biological process • DNA strand renaturation • neutrophil homeostasis • movement of cell or subcellular component • inflammatory response • signal transduction • cell surface receptor signaling pathway • response to X-ray • myoblast migration involved in skeletal muscle regeneration • peptide cross-linking • insulin secretion • keratinocyte differentiation • prostate gland development • endocrine pancreas development • positive regulation of vesicle fusion • positive regulation of prostaglandin biosynthetic process • response to estradiol • DNA duplex unwinding • positive regulation of neutrophil apoptotic process • DNA rewinding • gliogenesis • regulation of cell proliferation • response to drug • negative regulation of apoptotic process • response to peptide hormone • estrous cycle • alpha-beta T cell differentiation • arachidonic acid secretion • cellular response to hydrogen peroxide • hepatocyte differentiation • prolactin secretion • response to interleukin-1 • cellular response to glucocorticoid stimulus • neutrophil clearance • positive regulation of G1/S transition of mitotic cell cycle • negative regulation of phospholipase A2 activity • negative regulation of interleukin-8 secretion Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE ANXA1 201012 at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	301	16952
Ensembl	ENSG00000135046	ENSMUSG00000024659
UniProt	P04083	P10107
RefSeq (mRNA)	NM_000700	NM_010730
RefSeq (protein)	NP_000691	NP_034860
Location (UCSC)	Chr 9: 73.15 – 73.17 Mb	Chr 19: 20.37 – 20.39 Mb
PubMed search	[1]	[2]

Annexin A1, also known as lipocortin I, is a protein that is encoded by the ANXA1 gene in humans.

Function

Annexin A1 belongs to the annexin family of Ca²⁺-dependent phospholipid-binding proteins that have a molecular weight of approximately 35,000 to 40,000 and are preferentially located on the cytosolic face of the plasma membrane. Annexin A1 protein has an apparent relative molecular mass of 40 kDa with phospholipase A2 inhibitory activity.

Clinical significance

Effect on innate and adaptive immunity

Glucocorticoids (such as budesonide, cortisol, and beclomethasone) are a class of endogenous or synthetic anti-inflammatory steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. They are used in medicine to treat diseases caused by an overactive immune system, including allergies, asthma, autoimmune diseases, and sepsis. Because they suppress inflammatory pathways, long-term use of glucocorticoid drugs can lead to side-effects such as immunodeficiency and adrenal insufficiency.

The main mechanism of glucocorticoids' anti-inflammatory effects is to increase the synthesis and function of annexin A1. Annexin A1 both suppresses phospholipase A2, thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events (epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc.). In other words, glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes. They inhibit prostaglandin synthesis at the level of phospholipase A2 as well as at the level of cyclooxygenase/PGE isomerase (COX-1 and COX-2), the latter effect being much like that of NSAIDs, potentiating the anti-inflammatory effect.

In resting conditions, human and mouse immune cells such as neutrophils, monocytes, and macrophages contain high levels of annexin A1 in their cytoplasm. Following cell activation (for example, by neutrophil adhesion to endothelial-cell monolayers), annexin A1 is promptly mobilized to the cell surface and secreted. Annexin A1 promotes neutrophil detachment and apoptosis, and phagocytosis of apoptotic neutrophils by macrophages. On the other hand, it reduces the tendency of neutrophils to penetrate the endothelium of blood vessels.In vitro and in vivo analyses show that exogenous and endogenous annexin A1 counter-regulate the activities of innate immune cells, particularly extravasation and the generation of proinflammatory mediators, which ensures that a sufficient level of activation is reached but not exceeded.

Annexin A1 has important opposing properties during innate and adaptive immune responses: it inhibits innate immune cells and promotes T-cell activation. The activation of T cells results in the release of annexin A1 and the expression of its receptor. This pathway seems to fine-tune the strength of TCR signalling. Higher expression of annexin A1 during pathological conditions could increase the strength of TCR signalling through the mitogen-activated protein kinase signalling pathway, thereby causing a state of hyperactivation of T cells.

Inflammation

Since phospholipase A2 is required for the biosynthesis of the potent mediators of inflammation, prostaglandins, and leukotrienes, annexin A1 may have potential anti-inflammatory activity.

Glucocorticoids stimulate production of lipocortin. In this way, synthesis of eicosanoids are inhibited.

Cancer

Annexin A1 has been of interest for use as a potential anticancer drug. Upon induction by modified NSAIDS and other potent anti-inflammatory drugs, annexin A1 inhibits the NF-κB signal transduction pathway, which is exploited by cancerous cells to proliferate and avoid apoptosis. ANXA1 inhibits the activation of NF-κB by binding to the p65 subunit.

Leukemia

The gene for annexin A1 (ANXA1) is upregulated in hairy cell leukemia. ANXA1 protein expression is specific to hairy cell leukemia. Detection of ANXA1 (by immunocytochemical means) reportedly provides a simple, highly sensitive, and specific assay for the diagnosis of hairy cell leukemia.

Breast cancer

Exposure of MCF-7 breast cancer cells to high physiological levels (up to 100 nM) of estrogen lead to an up-regulation of annexin A1 expression partially through the activation of CREB, and dependent on activation of the estrogen receptor alpha. Treatment of MCF-7 cells with physiological levels of estrogen (1 nM) induced proliferation while high pregnancy levels of estrogen (100 nM) induced a growth arrest of MCF-7 cells. Silencing of ANXA1 with specific siRNA reverses the estrogen-dependent proliferation as well as growth arrest. ANXA1 is lost in clinical breast cancer, indicating that the anti-proliferative protective function of ANXA1 against high levels of estrogen may be lost in breast cancer. This data suggests that ANXA1 may act as a tumor suppressor gene and modulate the proliferative functions of estrogens.

Annexin A1 has also been shown to protect against DNA damage induced by heat in breast cancer cells, adding to the evidence that it has tumor suppressive and protective activities. When ANXA1 is silenced or lost in cancer, cells are more prone to DNA damage, indicating its unidentified diverse role in genome maintenance or integrity.

External links

• Annexin A1 at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.