HGNC Approved Gene Symbol: LACRT
Cytogenetic location: 12q13.2 Genomic coordinates (GRCh38) : 12:54,630,811-54,634,895 (from NCBI)
Lacritin is a small epithelial-selective human glycoprotein involved in mitogenesis (Wang et al., 2006).
By screening for gland-specific gene expression in a lacrimal gland cDNA library, Sanghi et al. (2001) identified and cloned LACRT. The deduced 138-amino acid protein has a calculated molecular mass of 14.3 kD. Lacritin contains a 19-amino acid signal peptide, which, upon cleavage, results in a secreted core protein of 12.3 kD. It has 6 putative O-glycosylation sites and an N-glycosylation site near the C terminus. Lacritin shares about 32% identity with the glycosaminoglycan region of neuroglycan C (606775), 30% identity with the globular region of fibulin-2 (135821), and high homology with mouse lacritin. Northern blot analysis revealed strong expression of a 760-bp transcript in lacrimal gland and weaker expression in submandibular and thyroid glands. No expression was observed in any other of the 50 tissues tested by RNA dot blot analysis. Immunolocalization revealed expression of lacritin in secretory granules of many acinar cells in lacrimal gland and in scattered acinar cells of salivary glands. Immunoreactivity was also seen within lumens of lacrimal and salivary ducts. By ELISA, lacritin was detected in human tears and, to a lesser extent, in saliva.
Sanghi et al. (2001) determined that recombinant lacritin enhanced basal secretion from rat lacrimal acinar cells and stimulated proliferation in quiescent human salivary gland cells in a dose-dependent manner. It promoted transient tyrosine phosphorylation of a 48-kD band in both cultures. In human corneal epithelial cells, the addition of lacritin induced rapid and sustained calcium waves that propagated throughout the cells. An ELISA-based binding assay revealed interaction between lacritin and collagen IV (see 120130), laminin-1 (see 150240), nidogen-1 (131390), fibronectin (135600), and vitronectin (193190).
Ma et al. (2006) found that syndecan-1 (SDC1; 186355) was required for lacritin-dependent mitogenesis and COX2 (PTGS2; 600262) expression. Lacritin targeted and interacted with cell surface SDC1 during an upstream step in lacritin mitogenic signaling. Binding was mediated by the lacritin C-terminal mitogenic domain and the SDC1 N terminus. However, binding of lacritin to SDC1 was independent of SDC1 heparan sulfate (HS) glycosaminoglycan chains, as the lacritin C terminus showed affinity for the SDC1 core protein but not the HS glycosaminoglycan chains. The HS-rich N terminus of SDC1 was partially deglycanated by heparanase-1 (HPSE; 604724), which exposed the SDC1 core protein to facilitate lacritin binding and signaling to mitogenic COX2.
Wang et al. (2006) found that lacritin was a cell-selective mitogen that targeted only a small subset of epithelia, but not fibroblasts or glia, for mitogenesis. Lacritin-dependent mitogenesis required the lacritin C terminus, which promoted Ca(2+) mobilization that required PLC (see 172420) and PKC-alpha (PRKCA; 176960). PKC-alpha played a central role in lacritin mitogenic signaling, and STIM1 (605921), but not TRPC1 (602343), was necessary for Ca(2+) influx. Lacritin stimulated translocation of PKC-alpha to the perinuclear Golgi region (PNG) and NFATC1 (600489) to the nucleus, both in a G protein-mediated and PLC-dependent manner. PNG-translocated PKC-alpha complexed with PLC-gamma-2 (PLCG2; 600220) to trigger 1,4,5-trisphosphate generation and Ca(2+) mobilization and activated downstream PLD1 (602382). As a result, lacritin signaling to PKC-alpha activated both Ca(2+)-NFAT and PLD-MTOR (601231) mitogenic pathways via STIM1-regulated Ca(2+) signaling.
Georgiev et al. (2021) found that lacritin monomer C-terminal processing, inclusive of cysteine, serine, and metalloproteinase activity, generated cationic amphipathic alpha-helical proteoforms. Such proteoforms in normal human tears were essential for the stability of light-refracting and immunoprotective tear film on eyes and prevented premature tear film collapse. When lacritin C-terminal proteoforms were selectively absent or deficient in tears, the tears behaved like dry-eye tears. These tears could be rescued by C-terminal lacritin peptides that were deficient in dry eye, as lacritin C-terminal proxy proteoforms restored normal viscoelasticity, possibly by acting as a surfactant and interacting with and stabilizing meibomian gland secretions. Repeated topical application in rabbits revealed a proteoform turnover time of 7 to 33 hours with gradual loss from human tear lipid that retained bioactivity without further processing. These results indicated that the processed C terminus of lacritin that was deficient or absent in dry eye tears appeared to play roles in preventing tear film collapse and as a natural slow release mechanism that restored epithelial homeostasis.
Sanghi et al. (2001) determined that the LACRT gene contains 5 exons and spans at least 12.4 kb.
By FISH, Sanghi et al. (2001) mapped the LACRT gene to chromosome 12q13.
Georgiev, G. A., Gh., M. S., Romano, J., Dias Teixeira, K. L., Struble, C., Ryan, D. S., Sia, R. K., Kitt, J. P., Harris, J. M., Hsu, K.-L., Libby, A., Odrich, M. G., Suarez, T., McKown, R. L., Laurie, G. W. Lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis. J. Biol. Chem. 296: 100070, 2021. [PubMed: 33187980] [Full Text: https://doi.org/10.1074/jbc.RA120.015833]
Ma, P., Beck, S. L., Raab, R. W., McKown, R. L., Coffman, G. L., Utani, A., Chirico, W. J., Rapraeger, A. C., Laurie, G. W. Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin. J. Cell Biol. 174: 1097-1106, 2006. Note: Erratum: J. Cell Biol. 192: 365 only, 2011. [PubMed: 16982797] [Full Text: https://doi.org/10.1083/jcb.200511134]
Sanghi, S., Kumar, R., Lumsden, A., Dickinson, D., Klepeis, V., Trinkaus-Randall, V., Frierson, H. F., Jr., Laurie, G. W. cDNA and genomic cloning of lacritin, a novel secretion enhancing factor from the human lacrimal gland. J. Molec. Biol. 310: 127-139, 2001. [PubMed: 11419941] [Full Text: https://doi.org/10.1006/jmbi.2001.4748]
Wang, J., Wang, N., Xie, J., Walton, S. C., McKown, R. L., Raab, R. W., Ma, P., Beck, S. L., Coffman, G. L., Hussaini, I. M., Laurie, G. W. Restricted epithelial proliferation by lacritin via PKC-alpha-dependent NFAT and mTOR pathways. J. Cell Biol. 174: 689-700, 2006. [PubMed: 16923831] [Full Text: https://doi.org/10.1083/jcb.200605140]