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transcriptional, fang, yang, plague, relationships, myocardial, leu125val, patients, 22336504, 1110, zhonghua, xin, xue, guan, bing, zhi, komatsu, nagano, sugiura, hagiwara, tanigawa, abiko, 22508864, 3416463, 1128, iai, 06098, 2570, infection, chen, duan, medicinal, ingredients, secretion, txb2, rat, 207481204, 19874221, 08923970902814129, 550, immunopharmacology, immunotoxicology, visser, polyneuropathy, myopathy, features, factors, 7557453, 17038033, 1468, 1331, 01498, 1203, european, neurology, spanaus, 19779041, 186585, 4583, ccl5, promotes, through, mai, guo, 24818768, 4109393, jconrel, 057, 187, controlled, targeted, www, businesswire, com, glycomimetics, announces, plans, initiate, trial, evaluate, gmi, 1359, winkler, barbier, nowlan, jacobsen, forristal, patton, regulates, hematopoietic, stem, dormancy, self, renewal, chemoresistance, 5593456, 23086476, 2969, 1651, price, burness, sivan, warner, cheng, lee, 2016, 340ra73, 31317455, 27225183, 8722465, scitranslmed, aad4059, translational, dormant, micrometastases, reside, niches, regulate, transit, taverna, moher, crowley, hynes, 14718670, 321755, 0307289101, 2004pnas, 763t, 763, null, beta5, 21209777, 2990482, s12307, 010, 0043, mediators, sipkins, runnels, côté, means, june, 7044, 15959517, 2570168, nature03703, 2005natur, 969s, 969, imaging, specialized, microdomains, tumour, engraftment, kang, 24140083, 3947254, pharmthera, 006, pharmacology, stromal, barthel, hays, yazawa, opperman, walley, 23149920, 3548951, 3264, 942, definition, determinants, laferrière, houle, carcinoma, sequential, involving, beta4, 22354589, 15387376, 1023, clin, 0000037708, 09420, lechpammer, long, woodward, kutok, 11632075, 15289332, 0691, 5261, sawada, tsuboi, fukuda, 7507108, 42275, 1425, differential, sublines, exhibiting, potentials, khatib, kontogiannea, fallavollita, jamison, meterissian, brodt, liver, 10096570, 1356, walz, aruffo, kolanus, seed, 1990, lex, determinant, 4984, 1990sci, 1132w, 1132, pober, mendrick, gimbrone, 1987, 2827173, 299728, 1987pnas, 9238b, inducible, 8th, edition, innate, chapter, aoki, laroy, fierro, hudson, 18579791, 2572800, 149641, 3744, henson, schnaar, 21329670, 061, 2011bbrc, 423s, 423, reynolds, e44529, 22970241, 3435295, 0044529, 744529s, mac, novel, delgadillo, cuckler, tees, benencia, 2015, c68, 25339657, 4281670, 00094, 308, isoforms, conditions, gout, tremblay, organ, selectivity, 11272581, 17891461, s10585, 007, 9096, descheny, trujillo, nguyen, 15994950, 1472661, 4653, 5750, kannagi, izawa, koike, miyazaki, kimura, 27761640, 15132763, 11159147, 1349, 7006, tb03219, 377, angiogenesis, zou, shinde, patil, dagia, smith, wargo, interliggi, c415, 15814589, 00289, kumar, philadelphia, saunders, 7216, 7335, pathologic, andrade, toloi, april, effects, soy, bean, huvec, 29123853, 22066752, 13697137, 582970, climacteric, e31874, 22384091, 3286450, 0031874, 731874h, modulation, eniola, adefeso, leeuwenberg, smeets, neefjes, shaffer, cinek, jeunhomme, 1992, 1283598, 1421640, 543, immunology, intercellular, new, york, garland, 8153, 4101, health, esko, freeze, stanley, bertozzi, hart, etzler, eds, 2nd, plainview, cold, spring, harbor, laboratory, press, 978, 87969, 770, essentials, glycobiology, somers, tang, shaw, camphausen, october, 12719907, 11081633, s0092, 8674, 00138, 467, insights, revealed, graves, crowther, chandran, rumberger, 6463, 4338500, 7509040, 367532a0, 1994natur, 532g, 532, williams, johnston, eddy, 1991, 1703529, 52267, 2466, chromosomal, grcm38, grch38, emerging, some, cancers, recurrences, formation, rupture, promoting, weakening, artery, walls, smoking, highly, enhanced, likelihood, inducing, dysfunction, upregulated, exposure, addictive, tobacco, regulated, increase, transcription, therefore, rrd, target, benefit, cigarette, csrc, arr1, nachrs, immunohistochemical, expressions, significantly, plaques, group, especially, neovascular, positively, density, reaction, plaque, associated, intima, study, umbilical, vein, increases, antibody, suppressed, lacking, had, reduced, deficient, selecin, suggest, host, trigger, exocytosis, fimbriae, ompa, cases, elevated, glucose, sepsis, normal, leads, swelling, linings, muscle, restricted, supply, underlying, pathology, cause, symptomatic, cipnm, traditional, medicines, downregulate, berberine, edema, beyond, direct, locally, enables, conjugated, nanoparticles, thioaptamers, containing, anti, payloads, addition, recruit, tumors, pro, enabling, trafficking, hold, promise, future, car, numerous, pieces, evidence, continue, support, minimally, affects, immediately, following, injection, genetic, deletion, furthermore, paradox, recently, trio, showing, constitutively, where, thought, perform, functions, vital, hijacked, specifically, metastasizing, supports, ongoing, efforts, complexity, discrepant, least, substrates, glycan, esl1, combinations, thereof, result, mechanisms, glg1, hematopoiesis, discovered, monocytic, hl60, led, induce, distant, would, enable, arrest, extravasate, form, since, correlates, increasing, multiple, normally, further, mechanistic, cascade, wherein, rates, velcro, allowing, engage, tight, circulating, similar, minutes, rather, produced, demand, progresses, injured, enter, activate, now, tightly, begin, making, way, chemokines, local, macrophages, over, nearby, expressing, correct, will, low, causing, internal, temporary, made, broken, recruiting, glycosphingolipid, neuacα2, glcnacβ1, 2galβ1, 4glcβcer, closely, dr3, mac2, cd44v, lamp2, lamp1, poorly, remains, firmly, demonstrated, detected, surfaces, tropism, both, should, bear, order, surrounding, counter, tyrosine, fgf, glycoreceptor, raising, possibility, initiating, include, members, families, granulocytes, recognizes, binds, sialylated, certain, eosinophils, memory, effector, association, thus, implicating, natural, killer, plant, compounds, estrogen, mixture, reduce, culture, supernatant, daidzein, biochanin, formononetin, genistein, affect, laminar, enhances, naïve, conditioned, setting, conferring, down, protect, reperfusion, forces, vesicles, called, transcribed, translated, transported, production, turn, takes, maximal, occurs, around, returns, baseline, weibel, palade, bodies, repeats, separate, whereas, cytosolic, derives, flanks, cassette, epidermal, repeat, units, intracellular, cytoplasmic, tail, cyto, three, dimensional, determined, resolution, reveals, limited, coordination, predicted, lectins, analysis, indicates, amino, side, chains, neunacα2, glcnac, tetrasaccharide, sushi, terminal, known, cd62, member, ucsc, np_035475, np_000441, nm_011345, nm_000450, mrna, q00690, p16581, uniprot, 20339, 6401, entrez, species, oma, ncbi, databases, orthologs, quickgo, amigo, actin, filament, based, internalization, heterophilic, via, extracellular, space, clathrin, coated, pit, raft, caveola, perinuclear, cytoplasm, cortical, cytoskeleton, cellular, metal, ion, sialic, oligosaccharide, ontology, biogps, lip, atrioventricular, ileal, semi, lunar, 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elial cells activated by cytokines like other selectins it plays an important part in inflammation in humans e selectin is encoded by the sele gene 5 structure edit e selectin has a cassette structure an n terminal c type lectin domain an egf epidermal growth factor like domain 6 sushi domain scr repeat units a transmembrane domain tm and an intracellular cytoplasmic tail cyto the three dimensional structure of the ligand binding region of human e selectin has been determined at 2 0 å resolution in 1994 6 the structure reveals limited contact between the two domains and a coordination of ca 2 not predicted from other c type lectins structure function analysis indicates a defined region and specific amino acid side chains that may be involved in ligand binding the e selectin bound to sialyl lewis x sle x neunacα2 3galβ1 4 fucα1 3 glcnac tetrasaccharide was solved in 2000 7 gene and regulation edit in humans e selectin is encoded by the sele gene its c type lectin domain egf like scr repeats and transmembrane domains are each encoded by separate exons whereas the e selectin cytosolic domain derives from two exons the e selectin locus flanks the l selectin locus on chromosome 1 8 different from p selectin which is stored in vesicles called weibel palade bodies e selectin is not stored in the cell and has to be transcribed translated and transported to the cell surface the production of e selectin is stimulated by the expression of p selectin which in turn is stimulated by tumor necrosis factor α tnfα interleukin 1 il 1 and lipopolysaccharide lps 9 10 it takes about two hours after cytokine recognition for e selectin to be expressed on the endothelial cell s surface maximal expression of e selectin occurs around 6 12 hours after cytokine stimulation and levels returns to baseline within 24 hours 10 shear forces are also found to affect e selectin expression a high laminar shear enhances acute endothelial cell response to interleukin 1β in naïve or shear conditioned endothelial cells as may be found in the pathological setting of ischemia reperfusion injury while conferring rapid e selectin down regulation to protect against chronic inflammation 11 phytoestrogens plant compounds with estrogen like biological activity such as genistein formononetin biochanin a and daidzein as well as a mixture of these phytoestrogens were found able to reduce e selectin as well as vcam 1 and icam 1 on cell surface and in culture supernatant 12 ligands edit e selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes e selectin ligands are expressed by neutrophils monocytes eosinophils memory effector t like lymphocytes and natural killer cells each of these cell types is found in acute and chronic inflammatory sites in association with expression of e selectin thus implicating e selectin in the recruitment of these cells to such inflammatory sites these carbohydrates include members of the lewis x and lewis a families found on monocytes granulocytes and t lymphocytes 13 the glycoprotein esl 1 present on neutrophils and myeloid cells was the first counter receptor for e selectin to be described it is a variant of the tyrosine kinase fgf glycoreceptor raising the possibility that its binding to e selectin is involved in initiating signaling in the bound cells p selectin glycoprotein ligand 1 psgl 1 derived from human neutrophils is also a high efficiency ligand for endothelium expressed e selectin under flow 14 it mediates the rolling of leukocytes on the activated endothelium surrounding an inflamed tissue both esl 1 and psgl 1 should bear sialyl lewis a x in order to bind e p selectins 15 e selectin is found to mediate the adhesion of tumor cells to endothelial cells by binding to e selectin ligands on the tumor cells e selectin ligands also play a role in cancer metastasis the role of these two e selectin ligands in metastasis in vivo is poorly defined and remains to be firmly demonstrated psgl 1 was detected on the surfaces of bone metastatic prostate tumor cells suggesting that it may have a functional role in the bone tropism of prostate tumor cells 16 in cancer cells cd44 death receptor 3 dr3 lamp1 and lamp2 were identified as e selectin ligands present on colon cancer cells 17 and cd44v mac2 bp and gangliosides were identified as e selectin ligands present on breast cancer cells 18 19 20 on human neutrophils the glycosphingolipid neuacα2 3galβ1 4glcnacβ1 3 galβ1 4 fucα1 3 glcnacβ1 3 2 galβ1 4glcnacβ1 3 2galβ1 4glcβcer and closely related structures are functional e selectin receptors 21 function edit role in inflammation edit during inflammation e selectin plays an important part in recruiting leukocytes to the site of injury the local release of cytokines il 1 and tnf α by macrophages in the inflamed tissue induces the over expression of e selectin on endothelial cells of nearby blood vessels 22 leukocytes in the blood expressing the correct ligand will bind with low affinity to e selectin also under the shear stress of blood flow causing the leukocytes to roll along the internal surface of the blood vessel as temporary interactions are made and broken as the inflammatory response progresses chemokines released by injured tissue enter the blood vessels and activate the rolling leukocytes which are now able to tightly bind to the endothelial surface and begin making their way into the tissue 13 p selectin has a similar function but is expressed on the endothelial cell surface within minutes as it is stored within the cell rather than produced on demand 13 role in cancer edit e selectin was first discovered as an transmembrane receptor induced in endothelial cells upon inflammatory stimulation which mediated adhesion of monocytic or hl60 leukemic cells 23 24 this led to the hypothesis that cancer cells secreted inflammatory cytokines such as il 1β or tnfα to induce e selectin at distant metastatic sites this induction would enable circulating tumor cells to arrest at stimulated sites roll along activated endothelium extravasate and form metastases 25 studies since have shown that e selectin binding to colon cancer cells correlates with increasing metastatic potential 26 and that cancer cells of multiple tumor types bind e selectin using glycoprotein or glycolipid ligands normally expressed on immune cells 27 28 studies have further described a mechanistic cascade wherein cancer cells first bind e selectin at shear flow rates e selectin binding results in a velcro like interaction allowing the cancer cells to engage higher affinity integrin binding that eventually results in a tight binding between tumor cells and the activated endothelium 29 30 while numerous pieces of in vitro and clinical evidence continue to support this hypothesis of e selectin mediated cancer metastasis in vivo studies of cancer metastasis have shown that e selectin knockout only minimally affects leukemic cell adhesion to bone immediately following injection 31 while experimental lung metastasis is not affected by the genetic deletion of e selectin 32 33 furthermore studies have also shown that primary tumor growth is increased in e selectin knockout mice 34 35 this paradox was more recently solved by a trio of studies showing that e selectin is only constitutively expressed in the bone marrow endothelium 36 where it is thought to perform functions vital to hematopoiesis 37 that are hijacked specifically by cells metastasizing to bone and not other sites 38 this data supports ongoing clinical efforts to inhibit breast cancer bone metastasis with e selectin blocking agents 39 the complexity of e selectin ligand biology may also play a role in these discrepant in vitro and in vivo results at least 15 different glycoprotein and glycolipid substrates for e selectin have been described on various cancer cells while only n glycan glg1 esl1 was shown to mediate bone metastasis 40 other ligands or combinations thereof may result in distinct mechanisms during cancer metastasis beyond a direct interaction with tumor cells e selectin induction in response to cytokines locally secreted by cancer cells enables specific tumor targeting of slex conjugated nanoparticles or thioaptamers containing anti tumor payloads 41 in addition e selectin may also function to recruit monocytes to primary tumors or lung metastases to promote an inflammatory pro tumor microenvironment 42 blocking these interactions or enabling trafficking of car t cells to e selectin positive sites may hold promise for future therapeutic development pathological relevance edit critical illness polyneuromyopathy edit in cases of elevated blood glucose levels such as in sepsis e selectin expression is higher than normal resulting in greater microvascular permeability the greater permeability leads to edema swelling of the skeletal endothelium blood vessel linings resulting in skeletal muscle ischemia restricted blood supply and eventually necrosis cell death this underlying pathology is the cause of the symptomatic disease critical illness polyneuromyopathy cipnm 43 traditional chinese herbal medicines like berberine downregulate e selectin 44 pathogen attachment edit study shows the adherence of porphyromonas gingivalis to human umbilical vein endothelial cells increases with the induction of e selectin expression by tnf α an antibody to e selectin and sialyl lewis x suppressed p gingivalis adherence to stimulated huvecs p gingivalis mutants lacking ompa like proteins pgm6 7 had reduced adherence to stimulated huvecs but fimbriae deficient mutants were not affected e selecin mediated p gingivalis adherence activated endothelial exocytosis these results suggest that the interaction between host e selectin and pathogen pgm6 7 mediates p gingivalis adherence to endothelial cells and may trigger vascular inflammation 45 acute coronary syndrome edit the immunohistochemical expressions of e selectin and pecam 1 were significantly increased at intima in vulnerable plaques of acute coronary syndrome acs group especially in neovascular endothelial cells and positively correlated with inflammatory cell density suggesting that pecam 1 and e selectin might play an important role in inflammatory reaction and development of vulnerable plaque e selectin ser128arg polymorphism is associated with acs and it might be a risk factor for acs 46 nicotine mediated induction edit smoking is highly correlated with enhanced likelihood of atherosclerosis by inducing endothelial dysfunction in endothelial cells various cell adhesion molecules including e selectin are shown to be upregulated upon exposure to nicotine the addictive component of tobacco smoke nicotine stimulated adhesion of monocytes to endothelial cells is dependent on the activation of α7 nachrs β arr1 and csrc regulated increase in e2f1 mediated transcription of e selectin gene therefore agents such as rrd 251 that can target activity of e2f1 may have potential therapeutic benefit against cigarette smoke induced atherosclerosis 47 cerebral aneurysm edit it s also found that e selectin expression increased in human ruptured cerebral aneurysm tissues e selectin might be an important factor involved in the process of cerebral aneurysm formation and rupture by promoting inflammation and weakening cerebral artery walls 48 as a biomarker edit e selectin is also an emerging biomarker for the metastatic potential of some cancers including colorectal cancer and recurrences 49 references edit 1 2 3 grch38 ensembl release 89 ensg00000007908 ensembl may 2017 1 2 3 grcm38 ensembl release 89 ensmusg00000026582 ensembl may 2017 human pubmed reference national center for biotechnology information u s national library of medicine mouse pubmed reference national center for biotechnology information u s national library of medicine collins t williams a johnston gi kim j eddy r shows t et al february 1991 structure and chromosomal location of the gene for endothelial leukocyte adhesion molecule 1 the journal of biological chemistry 266 4 2466 73 doi 10 1016 s0021 9258 18 52267 5 pmid 1703529 graves bj crowther rl chandran c rumberger jm li s huang ks et al february 1994 insight into e selectin ligand interaction from the crystal structure and mutagenesis of the lec egf domains nature 367 6463 532 8 bibcode 1994natur 367 532g doi 10 1038 367532a0 pmid 7509040 s2cid 4338500 somers ws tang j shaw gd camphausen rt october 2000 insights into the molecular basis of leukocyte tethering and rolling revealed by structures of p and e selectin bound to sle x and psgl 1 cell 103 3 467 79 doi 10 1016 s0092 8674 00 00138 0 pmid 11081633 s2cid 12719907 cummings rd 2008 selectins in varki a cummings rd esko jd freeze hh stanley p bertozzi cr hart gw etzler me eds essentials of glycobiology 2nd ed plainview n y cold spring harbor laboratory press isbn 978 0 87969 770 9 janeway c 2005 immunobiology the immune system in health and disease new york garland science isbn 0 8153 4101 6 1 2 leeuwenberg jf smeets ef neefjes jj shaffer ma cinek t jeunhomme tm et al december 1992 e selectin and intercellular adhesion molecule 1 are released by activated human endothelial cells in vitro immunology 77 4 543 9 pmc 1421640 pmid 1283598 huang rb eniola adefeso o 2012 shear stress modulation of il 1β induced e selectin expression in human endothelial cells plos one 7 2 e31874 bibcode 2012ploso 731874h doi 10 1371 journal pone 0031874 pmc 3286450 pmid 22384091 andrade cm sá mf toloi mr april 2012 effects of phytoestrogens derived from soy bean on expression of adhesion molecules on huvec climacteric 15 2 186 94 doi 10 3109 13697137 2011 582970 pmid 22066752 s2cid 29123853 1 2 3 robbins sl cotran rs kumar v collins t 1999 robbins pathologic basis of disease philadelphia wb saunders isbn 0 7216 7335 x zou x shinde patil vr dagia nm smith la wargo mj interliggi ka et al august 2005 psgl 1 derived from human neutrophils is a high efficiency ligand for endothelium expressed e selectin under flow american journal of physiology cell physiology 289 2 c415 24 doi 10 1152 ajpcell 00289 2004 pmid 15814589 kannagi r izawa m koike t miyazaki k kimura n may 2004 carbohydrate mediated cell adhesion in cancer metastasis and angiogenesis cancer science 95 5 377 84 doi 10 1111 j 1349 7006 2004 tb03219 x pmc 11159147 pmid 15132763 s2cid 27761640 dimitroff cj descheny l trujillo n kim r nguyen v huang w et al july 2005 identification of leukocyte e selectin ligands p selectin glycoprotein ligand 1 and e selectin ligand 1 on human metastatic prostate tumor cells cancer research 65 13 5750 60 doi 10 1158 0008 5472 can 04 4653 pmc 1472661 pmid 15994950 gout s tremblay pl huot j 2008 selectins and selectin ligands in extravasation of cancer cells and organ selectivity of metastasis clinical experimental metastasis 25 4 335 44 doi 10 1007 s10585 007 9096 4 pmid 17891461 s2cid 11272581 shirure vs liu t delgadillo lf cuckler cm tees df benencia f et al 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