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Nuclear factor of activated T-cells ( NFAT ) is a family of transcription factors shown to be important in immune response . One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells (as a regulator of T cell immune response) but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.

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64-449: LFU may refer to Lacrimal functional unit, primary source of lacritin in the body Least frequently used , algorithm Lebanese Forces – Executive Command , formerly known as "Lebanese Forces – Uprising" LFU 205 , monoplane Leopold-Franzens-Universität Innsbruck, Austria Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with

128-437: A 'proliferative field'. Lacritin also promotes secretion (including that of lipocalin-1 and lactoferrin ), cell survival and regeneration of the corneal epithelium after wounding. Three times daily topical treatment with C-terminal lacritin synthetic peptide 'Lacripep' (also known as 'N-94/C-6') at a 4 μM concentration regenerated corneal nerves and the ocular surface epithelium in the mouse Aire-/- dry eye model. This raises

192-656: A C-terminal fragment that is bactericidal. Most lacritin is produced by the lacrimal gland , including the accessory lacrimal gland of Wolfring. Some lacritin is produced by the meibomian gland , and by epithelial cells of the conjunctiva and cornea . Together these epithelia comprise much of the lacrimal functional unit (LFU). Dry eye is the most common disease of the LFU. A growing number of studies suggest that lacritin may be differentially downregulated in dry eye, including contact lens-related dry eye. Topical lacritin promotes tearing in rabbit preclinical studies. In

256-486: A binding site in the N-terminal region of syndecan-1's core protein. A G-protein-coupled receptor (GPCR) then appears to be ligated. Targeted cells signal to NFAT and mTOR if conditions are suitable for proliferation, or to AKT and FOXO3 under conditions of stress. Lacritin consists of 119 amino acids after cleavage of the N-terminal signal peptide and displays several predicted alpha helices , mostly in

320-405: A biphasic dose response that is optimal at 1 - 10 nM for human recombinant lacritin on human cells. Higher human lacritin concentrations are optimal on rat or mouse cells or on rabbit eyes. In a recent phase I/II clinical trial, a 22 μM topical dose of 'Lacripep' applied three times daily was effective at two weeks in primary Sjogren's Syndrome patients with an eye dryness score greater than 60,

384-437: A cell encounters a hypertonic environment NFAT5 is transported into the nucleus where it activates transcription of several osmoprotective genes. Therefore, it is expressed in the kidney medulla , skin and eyes but it can be also found in the thymus and activated lymphocytes. Although phosphorylation and dephosphorylation are key for controlling NFAT function by masking and unmasking nuclear localization signals, as shown by

448-507: A complex which consists of the transcription factor T-bet and NFAT stimulates production of IFN-γ, the most prominent cytokine of Th1 cells. The TCR activation also triggers, through NFAT:AP-1 complex, production of NFAT2/αA which is a short isoform of NFATc2 which lacks the C-terminal domain and is fulfilling a role of an autoregulator because it further enhances the activation of all effector T cells . For Th1 response NFATc1 seems to be

512-546: A complex with AP-1 (except in Tregs). This complex depending on the cytokine context then activates the key transcription factors of the distinct T cell subpopulations: T-bet for Th1 , GATA3 for Th2 , RORγ for Th17 and BATF for Tfh . T cells express almost all NFAT family members (except NFAT3). However, not every NFAT has the same significance for each subpopulation of T cells. Upon TCR stimulation and after subsequent activation of T-bet under Th1 cytokine conditions,

576-406: A conformational change that exposes a nuclear localization signal which promotes nuclear translocation. On the other hand, NFAT5 lacks a crucial part of the N-terminal regulatory domain which in the aforementioned group harbours the essential CN binding site. This makes NFAT5 activation completely independent of calcium signalling. It is, however, controlled by MAPK during osmotic stress . When

640-454: A decrease in IL-10 . However, some studies suggest a more important role of NFAT in B cells and therefore this topic is still not well understood and warrants further research. T cell anergy is induced by suboptimal stimulation conditions when for instance TCR is stimulated without appropriate costimulatory signals. Because of the missing co-stimulation AP-1 is absent and a NFAT:NFAT complex

704-846: A key role since mice with NFATc2 knockout show reduction in RORγ as well as in IL-17A, IL-17F, and IL-21. Treg cells are the only exceptions to the NFAT:AP-1 complex formation since after their TCR stimulation NFAT binds to SMAD3 instead of AP-1. This complex then activates FOXP3 transcription, a master gene regulator in Tregs. NFAT:FOXP3 complex then regulates Treg specific cytokine production. There are two main populations of Treg cells: natural Treg ( nTreg ) cells which develop in Thymus and induced Treg ( iTreg ) cells which develop from naive CD4+ T cells in

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768-573: A key role. Conversaly, NFATc2 together with NFAT2/αA are needed to revert the state of anergy or exhaustion. The Ca dependent calcineurin/NFAT signalling pathway has been found to be important in neuronal growth and axon guidance during vertebrate development. Each different class of NFAT contributes to different steps in the neural development. NFAT works with neurotrophic signalling to regulate axon outgrowth in several neuronal populations. Additionally, NFAT transcription complexes integrate neuronal growth with guidance cues such as netrin to facilitate

832-435: A restricted group of epithelial cells (including human corneal epithelia ), and not fibroblastic, glioma, or lymphoblastic cells. Cell surface proteoglycan syndecan-1 is partly responsible. Biotinylated cell surface proteins from a lacritin-responsive cell were incubated with lacritin under conditions of physiological salt. Those that bound lacritin were sequenced by mass spectrometry . Few bound. The most prominent

896-459: A score indicative of moderate to severe dry eye. Both corneal fluorescein staining and the symptom of burning/stinging were reduced. In keeping with a biphasic dose response, the 44 μM dose was largely ineffective. A biphasic dose response has a bell-shaped curve , with doses lower or higher than the dose optimum less effective. Other mitogens share this property. However, in secretion assays using monkey lacritin on monkey lacrimal acinar cells,

960-547: Is a 12.3 kDa glycoprotein encoded in humans by the LACRT gene . Lacritin's discovery emerged from a screen for factors that stimulate tear protein secretion. Lacritin is a secreted protein found in tears and saliva . Lacritin also promotes tear secretion, the proliferation and survival of epithelial cells, and corneal wound healing Lacritin is thus a multifunctional prosecretory mitogen with cell survival activity. Natural or bacterial cleavage of lacritin releases

1024-602: Is capable of fully activating NFAT through the CaM/CN mediated dephosphorylation as stated above. Although SOCE is the main activation mechanism of most of the proteins of the NFAT family, they can also be activated by an alternative pathway. This pathway was until now proofed only for NFATc2. In this alternative activation SOCE is insignificant as shown by the fact that cyclosporine (CsA), which inhibits CN mediated dephosphorylation, does not abrogate this pathway. The reason for this

1088-480: Is complete. Lacripep™ is lacritin synthetic peptide 'N-94/C-6'. NFAT The NFAT transcription factor family consists of five members: NFATc1 , NFATc2 , NFATc3 , NFATc4 , and NFAT5 . NFATc1 through NFATc4 are regulated by calcium signalling, and are known as the classical members of the NFAT family. NFAT5 is a more recently discovered member of the NFAT family that has special characteristics that differentiate it from other NFAT members. Calcium signalling

1152-551: Is critical to activation of NFATc1-4 because calmodulin (CaM), a well-known calcium sensor protein, activates the serine/threonine phosphatase calcineurin (CN). Activated CN binds to its binding site located in the N-terminal regulatory domain of NFATc1-4 and rapidly dephosphorylates the serine-rich region (SRR) and SP-repeats which are also present in the N-terminus of the NFAT proteins. This dephosphorylation results in

1216-472: Is differentially downregulated in mild to severe aqueous deficient dry eye, and in contact lens-related dry eye. In a larger trial, 95% of tears from patients with aqueous deficient dry eye were lacritin monomer deficient. Two studies that did not differentiate monomer from multimer did note any change of lacritin in dry eye. Topical treatment of eyes of dry eye mice (Aire knockout mouse model of dry eye) restored tearing, and suppressed both corneal staining and

1280-547: Is especially important for calcium influx because it binds to a IP3 receptor located in the membrane of the endoplasmic reticulum (ER). This causes a short sharp increase in calcium concentration in cytosol as the ions leave the ER through the IP3 receptor. However, this is not enough to activate NFAT signalling. The release of calcium ions from ER is sensed by STIM proteins which are ER transmembrane proteins. Under normal circumstances

1344-548: Is exported back to the cytosol where maintenance kinases finish the rephosphorylation in order to keep it in the inactivated state. NFAT proteins have weak DNA-binding capacity. Therefore, to effectively bind DNA, NFAT proteins must cooperate with other nuclear resident transcription factors generically referred to as NFATn. This important feature of NFAT transcription factors enables integration and coincidence detection of calcium signals with other signalling pathways such as ras-MAPK or PKC. In addition, this signalling integration

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1408-456: Is for breast cancer) and gene array studies, but some breast cancers appear to display elevated expression or LACRT gene amplification. iTRAQ analysis of tears from diabetics at different stages of disease detected relatively more lacritin, lysozyme, lipophilin A, lipocalin 1, immunoglobulin lambda chain and lactotransferrin in tears of patients with diabetic retinopathy. The analysis did not distinguish lacritin monomer from polymer, and proposed

1472-498: Is formed. This complex activates anergy associated genes like E3 ubiquitin ligases ( Cbl-b , ITCH , and GRAIL ), diacylglycerol kinase α (DGKα), and caspase 3 which promote the induction of T-cell anergy. Similar to T cell anergy is T cell exhaustion which is also caused by impaired formation of the NFAT:AP-1 complex but the underlying induction of exhaustion state is through chronic stimulation rather than suboptimal stimulation. In both anergy and exhaustion NFATc1 seems to play

1536-470: Is initiated. The upstream Gα i or Gα o signaling suggests the involvement of a G-protein-coupled receptor (GPCR). A candidate GPCR is under study. Syndecan-1 likely serves as a co-receptor. Binding lacritin may improve its GPCR affinity. Lacritin survival signaling is observed when cells are stressed. Lacritin promotes survival and homeostasis by transiently stimulating autophagy. The mechanism appears to involve lacritin stimulated acetylation of

1600-463: Is involved in tissue-specific gene expression during development. A screen of ncRNA sequences identified in EST sequencing projects discovered a 'ncRNA repressor of the nuclear factor of activated T cells' called NRON . NFAT-dependent promoters and enhancers tend to have 3-5 NFAT binding sites which indicates that higher order synergistic interactions between relevant proteins in a cooperative complex

1664-484: Is most highly expressed in the lacrimal gland , including the accessory lacrimal gland of Wolfring. Expression is moderate in salivary glands and slight in mammary (cancer but not or rarely normal), and thyroid glands . The salivary gland expression appears to be attributable to a discrete group of unidentified ductal-like cells. Some lacritin was reported in lung bronchoalveolar lavage and plasma. In lacrimal gland, polarized lacrimal acinar cells appear to be

1728-540: Is most similar to human lacritin among all non-primate sequences examined. Moreover, it is detectable in horse tears by immunoblotting or by ELISA. Antibodies directed to the C-, but not N-, terminus of human lacritin are most effective - in keeping with the predicted conservation of the C-terminal amphipathic alpha helix necessary for cell targeting. Tissue distribution has been examined in humans and monkeys. Lacritin

1792-402: Is needed for effective transcription. The best known class of these complexes is composed of NFAT and AP-1 or other bZIP proteins . This NFAT:AP-1 complex binds to the conventional Rel-family proteins DNA binding sites and is involved in gene transcription in immune cells. T-cell receptor (TCR) stimulation causes the dephosphorylation of NFAT which in almost every kind of T cell then forms

1856-583: Is not surprising that NFAT2 lymphocytes specific ablation causes a defect of the BCR-mediated proliferation but whether this phenotype is caused by sole dysregulation of Tfh or B cells or combination of both is uncertain. Although discovered in T cells it is becoming more obvious that NFAT is also expressed in different cell types. In B cells mainly NFATc1 and after activation also NFATc2 and NFAT2/αA are expressed and fulfil important functions like antigen presentation, proliferation, and apoptosis . Although

1920-450: Is possible that mobility is partially retarded by lacritin's amphipathic alpha helices. Predicted p I of lacritin's core protein is 5. Lacritin is subject to crosslinking by tissue transglutaminase , thereby giving rise to lacritin multimers including dimers and trimers. Crosslinking is initiated within 1 min in vitro, requiring as little as 0.1 nM lacritin. The ~0.6 micro molar level of tissue transglutaminase estimated in human tears

1984-586: Is sufficient to promote crosslinking. Crosslinking involves the donors lysine 82 and 85 and the acceptor glutamine 106. Glutamine 106 resides within the amphipathic alpha helix near the C-terminus responsible for binding the N-terminus of syndecan-1 . Accordingly, crosslinked lacritin binds syndecan-1 poorly and is inactive. Several lacritin splice variants have been detected in Aceview, from NEIBank EST data. Lacritin-b (11.1 kDa; p I 5.3) lacks

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2048-401: Is that another key element of lacritin targeting specificity is a G-protein-coupled receptor that would presumably form a cell surface targeting complex with SDC1. Involvement of a G-protein coupled receptor would explain the rapidity of lacritin signaling. Lacritin is a glycoprotein of the human tear film , and to a lesser extent of saliva, lung lavage and plasma. It is mainly produced by

2112-450: Is that it is activated through IL7R which leads to subsequent phosphorylation of single tyrosine in NFAT mediated by Jnk3 kinase a member of MAPK kinase subfamily. Nuclear import of NFAT and its subsequent export is dependent on the calcium level inside of a cell. If the calcium level drops, the exporting kinases in a nucleus such as PKA , CK1 or GSK-3β rephosphorylate NFAT. This causes that NFAT reverts into its inactive state and

2176-484: Is the only class of tear lipids apparently downregulated in dry eye. Lacritin mitogenic, survival and secretion signaling have been studied. Lacritin mitogenic signaling follows two pathways: Rapid dephosphorylation of PKCα causes it to transiently move from the cytoplasm to the area of the Golgi apparatus and peripheral nucleus. Here, it forms a complex with PKCα and PLCγ2 from which downstream mTOR and NFAT signaling

2240-628: The NFATc2 variety, so in mice lacking LRRK2, increased activation of NFATc2 was found in macrophages. This led to an increase in the NFAT-dependent cytokines that spark severe colitis attacks. NFAT also plays a role in Rheumatoid Arthritis (RA), an autoimmune disease that has a strong pro-inflammatory component. TNF-α , a pro-inflammatory cytokine, activates the calcineurin-NFAT pathway in macrophages . Additionally, inhibiting

2304-401: The lacrimal gland . Some lacritin also is produced by the meibomian gland , and also by epithelial cells of the conjunctiva and cornea . The lacritin gene ( LACRT ) is one of the most transcriptionally regulated genes in the human eye . Functional studies suggest a role in epithelial renewal of some non- germative epithelia. By flowing downstream through ducts , it may generate

2368-459: The mTOR pathway decreases joint inflammation and erosion, so the known interaction between mTOR pathway and NFAT presents a key to the inflammatory process of RA. Due to its essential role in the production of the T cell proliferative cytokine IL-2, NFAT signalling is an important pharmacological target for the induction of immunosuppression . CN inhibitors, which prevent the activation of NFAT, including CsA and tacrolimus (FK506), are used in

2432-560: The Aire knockout mouse model of dry eye (considered similar to human Sjogren's syndrome), topical lacritin restores pilocarpine-induced tearing, largely eliminates lissamine green staining and reduces the size of inflammatory foci in the lacrimal gland. Lacritin cell targeting is dependent on the cell surface heparan sulfate proteoglycan syndecan-1 (SDC1). Binding utilizes an enzyme-regulated 'off-on' switch in which active epithelial heparanase (HPSE) cleaves off heparan sulfate to expose

2496-487: The C-terminal half. Of these, the two C-terminal ones have been confirmed by circular dichroism. The most C-terminal alpha helix is amphipathic with hydrophobic and hydrophilic residues on opposite faces. The hydrophobic face is an important syndecan-1 binding element. PONDR (Predictor of Naturally Disordered Regions) predicts that the C-terminal and N-terminal halves are respectively ' ordered ' and 'disordered'. 11 - 12 predicted O-glycosylation sites populate

2560-509: The LFU is the primary source of lacritin in the body, and the eye the main target. Dry eye is the most common eye disease , affecting 5 - 6% of the population. Prevalence rises to 6 - 9.8% in postmenopausal women, and as high as 34% in the elderly. Tears lubricate the lid and are important for the refraction of light. Tears also promote epithelial health. Only a small fraction of the estimated 1543 proteins in tears are differentially deficient or upregulated in dry eye. Lacritin monomer

2624-430: The N-terminal half. The C-terminal amphipathic alpha helix is also the site of lacritin's only N-glycosylation site. In ' climatic droplet keratopathy ' this site is not glycosylated . Lacritin recombinantly generated in E. coli (no glycosylation) and lacritin in tears (glycosylated) differ in size with respective mobilities of ~18 and ~25 kDa by SDS-PAGE. With a predicted protein core molecular weight of 12.3 kDa, it

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2688-525: The STIM proteins bind calcium ions but if most of them are released from ER the bound ions are released from the STIM proteins as well. This causes them to oligomerize and subsequently interact with ORAI1 which is an indispensable protein of CRAC complex. This complex serves as a channel which selectively allows the influx of calcium ions from outside of a cell. This phenomenon is called store-operated calcium entry ( SOCE ). Only this longer inflow of calcium ions

2752-452: The agonist carbachol. When monkey lacrimal acinar cells are stressed with inflammatory cytokines (as occurs in dry eye), carbachol loses its capacity to promote the secretion of lipocalin. However, lacritin stimulates lipocalin secretion even in the presence of stress. Genomic sequencing assembled by Ensembl reveals the existence of putative lacritin orthologues in other species. Comparative genomic alignment suggests that horse lacritin

2816-474: The alpha helicity of lacritin's C-terminal amphipathic alpha helix and likely binds to the hydrophobic face. Syndecan-1 binds many growth factors through its long heparan sulfate side-chains. Yet, long heparan sulfate chains interfere with lacritin binding. Since syndecans are always decorated with heparan sulfate, this means that heparanase must be available to partially or completely cleave off heparan sulfate, allowing lacritin to bind. Indeed, no binding

2880-492: The amount of IgG1 and IgE . NFATc1 also plays an essential role as it forms a complex with GATA3 just like NFATc2. It further mediates the production of Th2 cytokines indirectly through regulation of CRTh2 . In line with Th1 and Th2 response, the stimulation of TCR under Th17 conditions elicits expression of RORγ. It subsequently binds to NFAT and stimulates the production of Th17 specific cytokines like IL-17A , IL-17F , IL-21 , IL-22 . In Th17 response probably NFATc2 plays

2944-643: The application of all as biomarkers. Tear lacritin monomer is barely detectable in the initial stage of infection by Fusarium solani in fungal keratitis. Also down regulated are tear lipocalin-1 and cystatin S. Fungal keratitis accounts for half of all corneal ulcers in Africa and India - the primary source of blindness in these countries. Phase II clinical trial of 'Lacripep™ in Subjects With Dry Eye Associated With Primary Sjögren's Syndrome' (NCT03226444)

3008-520: The bioactive lacritin synthetic peptides 'N-104', 'N-94' and 'N-94/C-6' from lacritin's C-terminus. Protease inhibitor studies suggest that processing of lacritin into C-terminal proteoforms requires a variety of tear proteases including cathepsin B , calpain , alanyl amino peptidase , arginyl aminopeptidase , MMP9 , MMP10 , cathepsin G , plasma kallikrein , plasmin , thrombin and trypsin . C-terminal proteoforms, like intact lacritin, are selectively deficient in dry eye tears. Lacritin targets

3072-453: The cationic face) appear to contribute to binding. Point mutagenesis of lacritin has narrowed the ligation site. This novel heparanase mechanism appears at first glance to be poor for ocular health since heparanase release from invading lymphocytes in the corneal stroma is inflammatory. Yet heparanase is a normal secretory product of the corneal epithelium. Lacritin-dependent mitogenesis is inhibitable by pertussis toxin ,. The implication

3136-784: The dose response appears to be sigmoidal with increasing lipocalin or lactoferrin secretion through a narrow 0.1, 0.3 and 1 μM dose range. Lacritin flows downstream from the lacrimal gland through ducts onto the eye . Artificial depletion of lacritin from normal human tears revealed that tears lacking lacritin are unable to promote the survival of ocular surface cells stressed with inflammatory cytokines. Human dry eye tears also lack this activity. However, dry eye tears supplemented with lacritin are fully protective. Similarly, tears artificially depleted of lacritin are deficient in bactericidal activity. The antibody used to deplete lacritin also depletes C-terminal proteoforms. These observations suggest that among all tear proteins, lacritin may be

3200-400: The formation of new synapses, helping to build neural circuits in the brain. NFAT is a known important player in both the developing and adult nervous system. NFAT plays a role in the regulation of inflammation of inflammatory bowel disease (IBD). In the gene that encodes LRRK2 (leucine-rich repeat kinase 2), a susceptibility locus for IBD was found. The kinase LRRK2 is an inhibitor for

3264-489: The high number of phosphorylation sites in the NFAT regulatory domain, this dephosphorylation cannot occur without an influx of calcium ions. The classical signalling relies on activation of phospholipase C (PLC) through different receptors like the T-cell receptor (TCR) ( PLCG1 ) or B-cell receptor (BCR) ( PLCG2 ). This activation leads to release of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). The IP3

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3328-419: The impairment of NFAT pathway has serious consequences in T cells, in B cells they seem to be rather mild. If for instance a specific B cell knockout of both STIM proteins is carried out, SOCE is completely abolished and therefore NFAT signalling as well. Although in these knockout B cells the resulting humoral response is very similar to B cells with no knockout, the complete abolishment of NFAT also brought about

3392-431: The master protector. Dry eye tears are subject to premature collapse, as are normal human tears artificially depleted of C-terminal proteoforms. In both cases, stability is largely restored by spiking in synthetic lacritin peptides N-94 or N-94/C-6 as proxy C-terminal proteoforms. Each peptide inserts rapidly into (O-acyl)-omega-hydroxy fatty acid ( OAHFA ) thought to reside at the aqueous lipid boundary in tears. OAHFA

3456-430: The most indispensable since knockout of NFATc1 in mice leads to extremely skewed Th2 response. Under Th2 stimulating conditions GATA3 is activated. It subsequently also interacts with NFAT and triggers production of Th2 typical cytokines like IL-4 , IL-5 and IL-13 . NFATc2 seems to be the most important for Th2 mediated response since its impairment lowers the amount of the aforementioned cytokines and also decreases

3520-449: The most prolific lacritin producers, as evidenced by strong staining of secretory granules in keeping with lacritin release after carbachol stimulation. Carbachol-dependent release involves PKC and calcium signaling. Some lacritin is produced by the meibomian gland , and also by epithelial cells of the conjunctiva and cornea that together with lacrimal gland comprise much of the lacrimal functional unit (LFU). Viewed collectively,

3584-1020: The periphery after their stimulation. iTreg cells seem to be highly dependent on NFATc1, 2 and 4 since deletion of any of these genes or their combination causes almost a complete loss of iTreg cells but not nTreg cells. In Tfh cells just like in Th1, Th2 and Th17 cells NFAT:AP-1 complex is formed. This complex afterwards activates transcription of BATF which then also binds to NFAT and together with other proteins like IRF4 commences production of Tfh indespensable molecules: CXCR5 , ICOS , Bcl6 and IL-21 . Tfh cells express high levels of NFATc1 and especially NFATc2 and NFAT2/αA which suggest an important role of NFATc2. Deletion of NFATc2 in T cells facilitates an increased number of Tfh cells and higher germinal center response probably due to dysregulation of CXCR5 and decreased number of T follicular regulatory (Tfr) cells. Since Tfh are tightly connected with humoral response any defect in them will project into B cells. Therefore, it

3648-402: The possibility that lacritin may have clinical applications in the treatment of dry eye , the most common eye disease . It also may be beneficial in promoting healing after LASIK or PRK surgery. Recent studies suggest that lacritin monomer is differentially down regulated in not only in dry eye , but also in blepharitis . Lacritin is an LFU prosecretory mitogen and survival factor with

3712-421: The sequence SIVEKSILTE. Lacritin-c (10.7 kDa; p I 4.6) displays a novel C-terminus that should be incapable of binding syndecan-1, and lacks cell survival activity. Splice variants are proteoforms . Proteoforms include proteolytically processed forms of lacritin. Top down mass spec sequencing revealed that human tears contain five N- and forty-two different C-terminal lacritin-a proteoforms. Some approximate

3776-470: The size of inflammatory foci in lacrimal glands. Lacritin monomer deficiency in tears of patients with blepharitis was also reported. Blepharitis is an inflammation of the eyelid often associated with dry eye. In climatic droplet keratopathy , N119 appears to be un- glycosylated . Also a normal breast cancer localization reported by some has not been replicated in Unigene (the ' mammary gland ' hit

3840-550: The title LFU . If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=LFU&oldid=748297232 " Category : Disambiguation pages Hidden categories: Short description is different from Wikidata All article disambiguation pages All disambiguation pages Lacritin 90070 n/a ENSG00000135413 n/a Q9GZZ8 n/a NM_033277 n/a NP_150593 n/a Lacritin

3904-630: The transcription factor FOXO3. Acetylated FOXO3 serves as a ligand for the autophagic mediator ATG101. Lacritin also promotes coupling of FOXO1 (that becomes acetylated with stress) with autophagic mediator ATG7. In the absence of lacritin, no coupling is observed. Thus acetylation alone is likely insufficient for FOXO1-ATG7 ligation, unlike an initial claim. Lacritin also restores oxidative phosphorylation and other metabolic events to rescue cells from stress. Lacritin stimulated secretion of tear proteins lipocalin and lactoferrin from monkey lacrimal acinar cells does not appear to be mediated by Ca , unlike

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3968-483: The treatment of rheumatoid arthritis , multiple sclerosis , Crohn's disease , and ulcerative colitis and to prevent the rejection of organ transplants . However, there is a toxicity associated with these drugs due to their ability to inhibit CN in non-immune cells, which limits their use in other situations that may call for immunosuppressing drug therapy, including allergy and inflammation. There are other compounds that target NFAT directly, as opposed to targeting

4032-440: Was detected from cells lacking heparanase after siRNA depletion. Binding was restored by spiking in exogenous heparanase or heparitinase. Thus, heparanase regulates lacritin function as an 'on-switch'. Exposed 3-O sulfated groups on heparanase-cleaved heparan sulfate (that likely interacts with the cationic face of lacritin's C-terminal amphipathic alpha helix), and an N-terminal chondroitin sulfate chain (likely also binds to

4096-460: Was syndecan-1 (SDC1). In confirmatory pull-down assays, binding was not shared with family members syndecan-2 or syndecan-4 , indicating that the protein core (and not the negatively charged heparan sulfate side-chains) was the main site of binding. Further analysis narrowed the site to syndecan-1's N-terminal 51 amino acids, and subsequently to the N-terminal sequence GAGAL that is conserved in syndecan-1's from different species. GAGAL promotes

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