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HGNC Approved Gene Symbol: ANXA2
Cytogenetic location: 15q22.2 Genomic coordinates (GRCh38) : 15:60,347,151-60,397,986 (from NCBI)
Huang et al. (1986) purified 2 phospholipase A2 (603603) inhibitors from placenta, ANXA1 (151690) and ANXA2, which they called lipocortin I and II, respectively. Western blot analysis detected ANXA2 at an apparent molecular mass of 35 kD in placenta and in all human and mammalian cell lines tested. Highest expression was found in epithelial cell lines. By screening placenta and monocytic cell line cDNA libraries using a nucleotide probe based on tryptic fragments, Huang et al. (1986) cloned ANXA2. ANXA2 and ANXA1 share about 50% amino acid homology, with highest homology in the central region, which in ANXA1 is important for phospholipase A2 inhibitory activity. Both proteins have a primary structure built from 4 repeats of a single unit, contain an N-terminal tyrosine phosphorylation site, and lack a signal sequence.
Annexin II, a major cellular substrate of the tyrosine kinase encoded by the SRC oncogene (190090), belongs to the annexin family of Ca(2+)-dependent phospholipid- and membrane-binding proteins. By screening a cDNA expression library generated from highly purified human osteoclast-like multinuclear cells (MNC) formed in long-term bone marrow cultures, Takahashi et al. (1994) identified a candidate clone that stimulated MNC formation. Sequence analysis showed that this cDNA encoded annexin II. Further studies yielded results suggesting that ANX2 is an autocrine factor that enhances osteoclast formation and bone resorption, a previously unknown function for this molecule.
Formation of the apical surface and lumen is a fundamental step in epithelial organ development. Martin-Belmonte et al. (2007) showed that Pten (601728) localized to the apical plasma membrane during epithelial morphogenesis to mediate enrichment of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) at this domain during cyst development in a 3-dimensional Madin-Darby canine kidney cell system. Ectopic PtdIns(4,5)P2 at the basolateral surface caused apical proteins to relocalize to the basolateral surface. Anx2 bound PtdIns(4,5)P2 and was recruited to the apical surface. Anx2 bound Cdc42 (116952) and recruited it to the apical surface, and Cdc42 in turn recruited the Par6 (607484)/atypical protein kinase C (aPKC; see 176982) complex to the apical surface. Loss of function of Pten, Anx2, Cdc42, or aPKC prevented normal development of the apical surface and lumen. Martin-Belmonte et al. (2007) concluded that PTEN, PtdIns(4,5)P2, ANX2, CDC42, and aPKC control apical plasma membrane and lumen formation.
ANXA2 is a binding partner for p11 (S100A10; 114085). Using mice and mouse cells and constructs, Oh et al. (2013) found that Anxa2 and p11 stabilized each other and engaged in a ternary complex with the chromatin-remodeling factor Smarca3 (HLTF; 603257). Determination of the crystal structure revealed that Anxa2 and p11 formed symmetrical dimers that bound 2 Smarca3 peptides aligned in a head-to-head arrangement. Smarca3 interacted with elements of both Anxa2 and p11. Inclusion of Smarca3 in the complex induced a conformational change in Anxa2-p11 that followed an induced-fit model. Smarca3 bound a B-box element in DNA, and inclusion of Anxa2-p11 increased binding of Smarca3 to an immobilized B-box element. Reporter gene assays in mouse N2A neuroblastoma cells revealed that Anxa2-p11 potentiated transcriptional activation by Smarca3. In cells, interaction of Smarca3 with Anxa2-p11 anchored Smarca3 to the nuclear matrix. Using knockout mice, Oh et al. (2013) showed that hippocampal p11 and Smarca3 were required for behavioral responses to selective serotonin reuptake inhibitors used as antidepressants.
Spano et al. (1990) isolated and characterized human genomic clones of the gene encoding lipocortin II (LIP2) and of 3 pseudogenes. The LIP2 gene is at least 40 kb long and consists of 13 exons. The 3 LIP2 pseudogenes show typical features of retroposons.
Spano et al. (1990) reported experiments which, together with the data published by Huebner et al. (1988), led them to conclude that the LIP2 gene is located on chromosome 15. Richard et al. (1994) presented an integration of the physical, expression, and genetic maps of human chromosome 15. They placed the ANXA2 gene in their region IV, i.e., 15q21-q22, thus confirming the previous localization.
Pseudogenes
By use of cDNAs in somatic cell hybrid analysis and in situ hybridization, Huebner et al. (1987, 1988) mapped the LPC2A (LIP2P1) locus to 4q21-q31. Spano et al. (1990) mapped the 3 LIP2 pseudogenes to chromosomes 4 (ANX2P1), 9 (ANX2P2) and 10 (ANX2P3). The coexistence on chromosome 9 of the LIP1 gene (151690) and a LIP pseudogene was considered fortuitous.
By means of a lipocortin cDNA in somatic cell hybrid analysis and in situ chromosome hybridization, Huebner et al. (1987, 1988) mapped LPC2B (ANX2P2) to chromosome 9. Thus, LPC1 and LPC2B are syntenic. LPC2B is located proximal to ABL (189980). Calpactin I is a synonym for lipocortin II.
Huebner et al. (1987, 1988) mapped the LPC2C (ANX2P3) gene to 10q21-q22.
Ling et al. (2004) generated Anxa2-null mice that displayed deposition of fibrin in the microvasculature and incomplete clearance of injury-induced arterial thrombi. The null mice demonstrated normal lysis of fibrin-containing plasma clots, but tissue plasminogen activator (tPA; 173370)-dependent plasmin generation at the endothelial cell surface was markedly deficient. Directed migration of Anxa2-null endothelial cells through fibrin and collagen lattices in vitro was also reduced, and a peptide mimicking ANXA2 sequences necessary for tPA binding blocked endothelial cell invasion of Matrigel implants in wildtype mice. In addition, Anxa2-null mice displayed markedly diminished neovascularization of fibroblast growth factor (see 131220)-stimulated cornea and of oxygen-primed neonatal retina. Capillary sprouting from Anxa2-deficient aortic ring explants was markedly reduced in association with severe impairment of activation of metalloproteinase-9 (MMP9; 120361) and -13 (MMP13; 600108). Ling et al. (2004) concluded that ANXA2 is a regulator of cell surface plasmin generation and that impaired endothelial cell fibrinolytic activity constitutes a barrier to effective neoangiogenesis.
Huang, K.-S., Wallner, B. P., Mattaliano, R. J., Tizard, R., Burne, C., Frey, A., Hession, C., McGray, P., Sinclair, L. K., Chow, E. P., Browning, J. L., Ramachandran, K. L., Tang, J., Smart, J. E., Pepinsky, R. B. Two human 35 kd inhibitors of phospholipase A2 are related to substrates of pp60(v-src) and of the epidermal growth factor receptor/kinase. Cell 46: 191-199, 1986. [PubMed: 3013422] [Full Text: https://doi.org/10.1016/0092-8674(86)90736-1]
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]
Ling, Q., Jacovina, A. T., Deora, A., Febbraio, M., Simantov, R., Silverstein, R. L., Hempstead, B., Mark, W. H., Hajjar, K. A. Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo. J. Clin. Invest. 113: 38-48, 2004. [PubMed: 14702107] [Full Text: https://doi.org/10.1172/JCI19684]
Martin-Belmonte, F., Gassama, A., Datta, A., Yu, W., Rescher, U., Gerke, V., Mostov, K. PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 128: 383-397, 2007. [PubMed: 17254974] [Full Text: https://doi.org/10.1016/j.cell.2006.11.051]
Oh, Y.-S., Gao, P., Lee, K.-W., Ceglia, I., Seo, J.-S., Zhang, X., Ahn, J.-H., Chait, B. T., Patel, D. J., Kim, Y., Greengard, P. SMARCA3, a chromatin-remodeling factor, is required for p11-dependent antidepressant action. Cell 152: 831-843, 2013. [PubMed: 23415230] [Full Text: https://doi.org/10.1016/j.cell.2013.01.014]
Richard, I., Broux, O., Chiannilkulchai, N., Fougerousse, F., Allamand, V., Bourg, N., Brenguier, L., Devaud, C., Pasturaud, P., Roudaut, C., Lorenzo, F., Sebastiani-Kabatchis, C., Schultz, R. A., Polymeropoulos, M. H., Gyapay, G., Auffray, C., Beckmann, J. S. Regional localization of human chromosome 15 loci. Genomics 23: 619-627, 1994. [PubMed: 7851890] [Full Text: https://doi.org/10.1006/geno.1994.1550]
Spano, F., Raugei, G., Palla, E., Colella, C., Melli, M. Characterization of the human lipocortin-2-encoding multigene family: its structure suggests the existence of a short amino acid unit undergoing duplication. Gene 95: 243-251, 1990. [PubMed: 2174397] [Full Text: https://doi.org/10.1016/0378-1119(90)90367-z]
Takahashi, S., Reddy, S. V., Chirgwin, J. M., Devlin, R., Haipek, C., Anderson, J., Roodman, G. D. Cloning and identification of annexin II as an autocrine/paracrine factor that increases osteoclast formation and bone resorption. J. Biol. Chem. 269: 28696-28701, 1994. [PubMed: 7961821]