Leukocyte extravasation is a rigorously controlled process that guides white cell movement from the vascular lumen to sites of tissue inflammation. The powerful adhesive interactions that are required for leukocytes to withstand local flow at the vessel wall is a multistep process mediated by different adhesion molecules. Platelets adhered to injured vessel walls form strong adhesive substrates for leukocytes. For instance, the initial tethering and rolling of leukocytes over the site of injury are mediated by reversible binding of selectins to their cognate cell-surface glycoconjugates.
Endothelial cells are tightly connected through various proteins, which regulate the organization of the junctional complex and bind to cytoskeletal proteins or cytoplasmic interaction partners that allow the transfer of intracellular signals. An important role for these junctional proteins in governing the transendothelial migration of leukocytes under normal or inflammatory conditions has been established.<p>
This pathway describes some of the key interactions that assist in the process of platelet and leukocyte interaction with the endothelium, in response to injury.
Jones N, Dumont DJ.; ''The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R.''; PubMedEurope PMCScholia
Huang H, Cruz F, Bazzoni G.; ''Junctional adhesion molecule-A regulates cell migration and resistance to shear stress.''; PubMedEurope PMCScholia
Hafizi S, Dahlbäck B.; ''Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases.''; PubMedEurope PMCScholia
Yan Q, Malashkevich VN, Fedorov A, Fedorov E, Cao E, Lary JW, Cole JL, Nathenson SG, Almo SC.; ''Structure of CD84 provides insight into SLAM family function.''; PubMedEurope PMCScholia
Hua CT, Gamble JR, Vadas MA, Jackson DE.; ''Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates.''; PubMedEurope PMCScholia
Esmon CT.; ''The roles of protein C and thrombomodulin in the regulation of blood coagulation.''; PubMedEurope PMCScholia
Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R.; ''MIF signal transduction initiated by binding to CD74.''; PubMedEurope PMCScholia
Guo H, Li R, Zucker S, Toole BP.; ''EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface.''; PubMedEurope PMCScholia
Kirk P, Wilson MC, Heddle C, Brown MH, Barclay AN, Halestrap AP.; ''CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression.''; PubMedEurope PMCScholia
Wanaguru M, Crosnier C, Johnson S, Rayner JC, Wright GJ.; ''Biochemical analysis of the Plasmodium falciparum erythrocyte-binding antigen-175 (EBA175)-glycophorin-A interaction: implications for vaccine design.''; PubMedEurope PMCScholia
Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM.; ''An antagonist decoy receptor and a death domain-containing receptor for TRAIL.''; PubMedEurope PMCScholia
Kontos CD, Stauffer TP, Yang WP, York JD, Huang L, Blanar MA, Meyer T, Peters KG.; ''Tyrosine 1101 of Tie2 is the major site of association of p85 and is required for activation of phosphatidylinositol 3-kinase and Akt.''; PubMedEurope PMCScholia
Messmer B, Eissmann P, Stark S, Watzl C.; ''CD48 stimulation by 2B4 (CD244)-expressing targets activates human NK cells.''; PubMedEurope PMCScholia
Kalinowska A, Losy J.; ''PECAM-1, a key player in neuroinflammation.''; PubMedEurope PMCScholia
Xu Y, Yu Q.; ''Angiopoietin-1, unlike angiopoietin-2, is incorporated into the extracellular matrix via its linker peptide region.''; PubMedEurope PMCScholia
Pumphrey NJ, Taylor V, Freeman S, Douglas MR, Bradfield PF, Young SP, Lord JM, Wakelam MJ, Bird IN, Salmon M, Buckley CD.; ''Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31.''; PubMedEurope PMCScholia
Yoshida S, Shibata M, Yamamoto S, Hagihara M, Asai N, Takahashi M, Mizutani S, Muramatsu T, Kadomatsu K.; ''Homo-oligomer formation by basigin, an immunoglobulin superfamily member, via its N-terminal immunoglobulin domain.''; PubMedEurope PMCScholia
Trzpis M, McLaughlin PM, de Leij LM, Harmsen MC.; ''Epithelial cell adhesion molecule: more than a carcinoma marker and adhesion molecule.''; PubMedEurope PMCScholia
Huang L, Turck CW, Rao P, Peters KG.; ''GRB2 and SH-PTP2: potentially important endothelial signaling molecules downstream of the TEK/TIE2 receptor tyrosine kinase.''; PubMedEurope PMCScholia
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Hafizi S, Dahlbäck B.; ''Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily.''; PubMedEurope PMCScholia
Bradfield PF, Scheiermann C, Nourshargh S, Ody C, Luscinskas FW, Rainger GE, Nash GB, Miljkovic-Licina M, Aurrand-Lions M, Imhof BA.; ''JAM-C regulates unidirectional monocyte transendothelial migration in inflammation.''; PubMedEurope PMCScholia
Jackson SP, Mistry N, Yuan Y.; ''Platelets and the injured vessel wall-- "rolling into action": focus on glycoprotein Ib/V/IX and the platelet cytoskeleton.''; PubMedEurope PMCScholia
Farias E, Lu M, Li X, Schnapp LM.; ''Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway.''; PubMedEurope PMCScholia
Litvinov SV, Velders MP, Bakker HA, Fleuren GJ, Warnaar SO.; ''Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule.''; PubMedEurope PMCScholia
Mayer DC, Cofie J, Jiang L, Hartl DL, Tracy E, Kabat J, Mendoza LH, Miller LH.; ''Glycophorin B is the erythrocyte receptor of Plasmodium falciparum erythrocyte-binding ligand, EBL-1.''; PubMedEurope PMCScholia
Ordonez C, Zhai AB, Camacho-Leal P, Demarte L, Fan MM, Stanners CP.; ''GPI-anchored CEA family glycoproteins CEA and CEACAM6 mediate their biological effects through enhanced integrin alpha5beta1-fibronectin interaction.''; PubMedEurope PMCScholia
Melchers F, Karasuyama H, Haasner D, Bauer S, Kudo A, Sakaguchi N, Jameson B, Rolink A.; ''The surrogate light chain in B-cell development.''; PubMedEurope PMCScholia
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Yurchenko V, Zybarth G, O'Connor M, Dai WW, Franchin G, Hao T, Guo H, Hung HC, Toole B, Gallay P, Sherry B, Bukrinsky M.; ''Active site residues of cyclophilin A are crucial for its signaling activity via CD147.''; PubMedEurope PMCScholia
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Foster DC, Sprecher CA, Holly RD, Gambee JE, Walker KM, Kumar AA.; ''Endoproteolytic processing of the dibasic cleavage site in the human protein C precursor in transfected mammalian cells: effects of sequence alterations on efficiency of cleavage.''; PubMedEurope PMCScholia
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Ostermann G, Weber KS, Zernecke A, Schröder A, Weber C.; ''JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes.''; PubMedEurope PMCScholia
Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD.; ''Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning.''; PubMedEurope PMCScholia
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Tangye SG, Phillips JH, Lanier LL.; ''The CD2-subset of the Ig superfamily of cell surface molecules: receptor-ligand pairs expressed by NK cells and other immune cells.''; PubMedEurope PMCScholia
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Wilson MC, Meredith D, Halestrap AP.; ''Fluorescence resonance energy transfer studies on the interaction between the lactate transporter MCT1 and CD147 provide information on the topology and stoichiometry of the complex in situ.''; PubMedEurope PMCScholia
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McDonald KJ, Cameron AJ, Allen JM, Jardine AG.; ''Expression of Fc alpha/mu receptor by human mesangial cells: a candidate receptor for immune complex deposition in IgA nephropathy.''; PubMedEurope PMCScholia
da Costa Martins P, García-Vallejo JJ, van Thienen JV, Fernandez-Borja M, van Gils JM, Beckers C, Horrevoets AJ, Hordijk PL, Zwaginga JJ.; ''P-selectin glycoprotein ligand-1 is expressed on endothelial cells and mediates monocyte adhesion to activated endothelium.''; PubMedEurope PMCScholia
Newton JP, Buckley CD, Jones EY, Simmons DL.; ''Residues on both faces of the first immunoglobulin fold contribute to homophilic binding sites of PECAM-1/CD31.''; PubMedEurope PMCScholia
Loughna S, Sato TN.; ''Angiopoietin and Tie signaling pathways in vascular development.''; PubMedEurope PMCScholia
Wilkins AL, Yang W, Yang JJ.; ''Structural biology of the cell adhesion protein CD2: from molecular recognition to protein folding and design.''; PubMedEurope PMCScholia
Langer HF, Daub K, Braun G, Schönberger T, May AE, Schaller M, Stein GM, Stellos K, Bueltmann A, Siegel-Axel D, Wendel HP, Aebert H, Roecken M, Seizer P, Santoso S, Wesselborg S, Brossart P, Gawaz M.; ''Platelets recruit human dendritic cells via Mac-1/JAM-C interaction and modulate dendritic cell function in vitro.''; PubMedEurope PMCScholia
Tsuji M, Ezumi Y, Arai M, Takayama H.; ''A novel association of Fc receptor gamma-chain with glycoprotein VI and their co-expression as a collagen receptor in human platelets.''; PubMedEurope PMCScholia
Newton JP, Hunter AP, Simmons DL, Buckley CD, Harvey DJ.; ''CD31 (PECAM-1) exists as a dimer and is heavily N-glycosylated.''; PubMedEurope PMCScholia
Khunkaewla P, Schiller HB, Paster W, Leksa V, Cermák L, Andera L, Horejsí V, Stockinger H.; ''LFA-1-mediated leukocyte adhesion regulated by interaction of CD43 with LFA-1 and CD147.''; PubMedEurope PMCScholia
Han DC, Shen TL, Guan JL.; ''The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions.''; PubMedEurope PMCScholia
Piali L, Hammel P, Uherek C, Bachmann F, Gisler RH, Dunon D, Imhof BA.; ''CD31/PECAM-1 is a ligand for alpha v beta 3 integrin involved in adhesion of leukocytes to endothelium.''; PubMedEurope PMCScholia
Schröder AK, Uciechowski P, Fleischer D, Rink L.; ''Crosslinking of CD66B on peripheral blood neutrophils mediates the release of interleukin-8 from intracellular storage.''; PubMedEurope PMCScholia
Bayas MV, Kearney A, Avramovic A, van der Merwe PA, Leckband DE.; ''Impact of salt bridges on the equilibrium binding and adhesion of human CD2 and CD58.''; PubMedEurope PMCScholia
Ward NL, Dumont DJ.; ''The angiopoietins and Tie2/Tek: adding to the complexity of cardiovascular development.''; PubMedEurope PMCScholia
Brakebusch C, Fässler R.; ''beta 1 integrin function in vivo: adhesion, migration and more.''; PubMedEurope PMCScholia
Ostermann G, Fraemohs L, Baltus T, Schober A, Lietz M, Zernecke A, Liehn EA, Weber C.; ''Involvement of JAM-A in mononuclear cell recruitment on inflamed or atherosclerotic endothelium: inhibition by soluble JAM-A.''; PubMedEurope PMCScholia
Master Z, Jones N, Tran J, Jones J, Kerbel RS, Dumont DJ.; ''Dok-R plays a pivotal role in angiopoietin-1-dependent cell migration through recruitment and activation of Pak.''; PubMedEurope PMCScholia
Barton WA, Tzvetkova D, Nikolov DB.; ''Structure of the angiopoietin-2 receptor binding domain and identification of surfaces involved in Tie2 recognition.''; PubMedEurope PMCScholia
Martin M, Romero X, de la Fuente MA, Tovar V, Zapater N, Esplugues E, Esplugues E, Pizcueta P, Bosch J, Engel P.; ''CD84 functions as a homophilic adhesion molecule and enhances IFN-gamma secretion: adhesion is mediated by Ig-like domain 1.''; PubMedEurope PMCScholia
Neumann S, Hasenauer J, Pollak N, Scheurich P.; ''Dominant negative effects of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor 4 on TRAIL receptor 1 signaling by formation of heteromeric complexes.''; PubMedEurope PMCScholia
Deora AA, Philp N, Hu J, Bok D, Rodriguez-Boulan E.; ''Mechanisms regulating tissue-specific polarity of monocarboxylate transporters and their chaperone CD147 in kidney and retinal epithelia.''; PubMedEurope PMCScholia
DiScipio RG, Davie EW.; ''Characterization of protein S, a gamma-carboxyglutamic acid containing protein from bovine and human plasma.''; PubMedEurope PMCScholia
Sachs UJ, Andrei-Selmer CL, Maniar A, Weiss T, Paddock C, Orlova VV, Choi EY, Newman PJ, Preissner KT, Chavakis T, Santoso S.; ''The neutrophil-specific antigen CD177 is a counter-receptor for platelet endothelial cell adhesion molecule-1 (CD31).''; PubMedEurope PMCScholia
Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J.; ''The structural basis of the activation of Ras by Sos.''; PubMedEurope PMCScholia
Moriwaki H, Kume N, Sawamura T, Aoyama T, Hoshikawa H, Ochi H, Nishi E, Masaki T, Kita T.; ''Ligand specificity of LOX-1, a novel endothelial receptor for oxidized low density lipoprotein.''; PubMedEurope PMCScholia
Pushkarsky T, Yurchenko V, Vanpouille C, Brichacek B, Vaisman I, Hatakeyama S, Nakayama KI, Sherry B, Bukrinsky MI.; ''Cell surface expression of CD147/EMMPRIN is regulated by cyclophilin 60.''; PubMedEurope PMCScholia
Xie Q, Matsunaga S, Niimi S, Ogawa S, Tokuyasu K, Sakakibara Y, Machida S.; ''Human lectin-like oxidized low-density lipoprotein receptor-1 functions as a dimer in living cells.''; PubMedEurope PMCScholia
Cartron JP, Rahuel C.; ''Human erythrocyte glycophorins: protein and gene structure analyses.''; PubMedEurope PMCScholia
Merzaban JS, Burdick MM, Gadhoum SZ, Dagia NM, Chu JT, Fuhlbrigge RC, Sackstein R.; ''Analysis of glycoprotein E-selectin ligands on human and mouse marrow cells enriched for hematopoietic stem/progenitor cells.''; PubMedEurope PMCScholia
Kisiel W.; ''Human plasma protein C: isolation, characterization, and mechanism of activation by alpha-thrombin.''; PubMedEurope PMCScholia
Wen DZ, Dittman WA, Ye RD, Deaven LL, Majerus PW, Sadler JE.; ''Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene.''; PubMedEurope PMCScholia
Barclay AN, Brown MH.; ''The SIRP family of receptors and immune regulation.''; PubMedEurope PMCScholia
Audero E, Cascone I, Maniero F, Napione L, Arese M, Lanfrancone L, Bussolino F.; ''Adaptor ShcA protein binds tyrosine kinase Tie2 receptor and regulates migration and sprouting but not survival of endothelial cells.''; PubMedEurope PMCScholia
Foster D, Davie EW.; ''Characterization of a cDNA coding for human protein C.''; PubMedEurope PMCScholia
Peters KG, Kontos CD, Lin PC, Wong AL, Rao P, Huang L, Dewhirst MW, Sankar S.; ''Functional significance of Tie2 signaling in the adult vasculature.''; PubMedEurope PMCScholia
Buckley CD, Doyonnas R, Newton JP, Blystone SD, Brown EJ, Watt SM, Simmons DL.; ''Identification of alpha v beta 3 as a heterotypic ligand for CD31/PECAM-1.''; PubMedEurope PMCScholia
Becker BF, Heindl B, Kupatt C, Zahler S.; ''Endothelial function and hemostasis.''; PubMedEurope PMCScholia
Ludwig RJ, Zollner TM, Santoso S, Hardt K, Gille J, Baatz H, Johann PS, Pfeffer J, Radeke HH, Schön MP, Kaufmann R, Boehncke WH, Podda M.; ''Junctional adhesion molecules (JAM)-B and -C contribute to leukocyte extravasation to the skin and mediate cutaneous inflammation.''; PubMedEurope PMCScholia
Jones N, Master Z, Jones J, Bouchard D, Gunji Y, Sasaki H, Daly R, Alitalo K, Dumont DJ.; ''Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration.''; PubMedEurope PMCScholia
Mandicourt G, Iden S, Ebnet K, Aurrand-Lions M, Imhof BA.; ''JAM-C regulates tight junctions and integrin-mediated cell adhesion and migration.''; PubMedEurope PMCScholia
Moore KL, Eaton SF, Lyons DE, Lichenstein HS, Cummings RD, McEver RP.; ''The P-selectin glycoprotein ligand from human neutrophils displays sialylated, fucosylated, O-linked poly-N-acetyllactosamine.''; PubMedEurope PMCScholia
Santoso S, Sachs UJ, Kroll H, Linder M, Ruf A, Preissner KT, Chavakis T.; ''The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1.''; PubMedEurope PMCScholia
Yoshida H, Kondratenko N, Green S, Steinberg D, Quehenberger O.; ''Identification of the lectin-like receptor for oxidized low-density lipoprotein in human macrophages and its potential role as a scavenger receptor.''; PubMedEurope PMCScholia
Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, Tanaka T, Miwa S, Katsura Y, Kita T, Masaki T.; ''An endothelial receptor for oxidized low-density lipoprotein.''; PubMedEurope PMCScholia
Jackson DE, Ward CM, Wang R, Newman PJ.; ''The protein-tyrosine phosphatase SHP-2 binds platelet/endothelial cell adhesion molecule-1 (PECAM-1) and forms a distinct signaling complex during platelet aggregation. Evidence for a mechanistic link between PECAM-1- and integrin-mediated cellular signaling.''; PubMedEurope PMCScholia
Cicmil M, Thomas JM, Sage T, Barry FA, Leduc M, Bon C, Gibbins JM.; ''Collagen, convulxin, and thrombin stimulate aggregation-independent tyrosine phosphorylation of CD31 in platelets. Evidence for the involvement of Src family kinases.''; PubMedEurope PMCScholia
Heller M, von der Ohe M, Kleene R, Mohajeri MH, Schachner M.; ''The immunoglobulin-superfamily molecule basigin is a binding protein for oligomannosidic carbohydrates: an anti-idiotypic approach.''; PubMedEurope PMCScholia
Schober A, Weber C.; ''Mechanisms of monocyte recruitment in vascular repair after injury.''; PubMedEurope PMCScholia
Cunningham SA, Rodriguez JM, Arrate MP, Tran TM, Brock TA.; ''JAM2 interacts with alpha4beta1. Facilitation by JAM3.''; PubMedEurope PMCScholia
Graves BJ, Crowther RL, Chandran C, Rumberger JM, Li S, Huang KS, Presky DH, Familletti PC, Wolitzky BA, Burns DK.; ''Insight into E-selectin/ligand interaction from the crystal structure and mutagenesis of the lec/EGF domains.''; PubMedEurope PMCScholia
Bos MP, Grunert F, Belland RJ.; ''Differential recognition of members of the carcinoembryonic antigen family by Opa variants of Neisseria gonorrhoeae.''; PubMedEurope PMCScholia
Zen K, Liu Y, McCall IC, Wu T, Lee W, Babbin BA, Nusrat A, Parkos CA.; ''Neutrophil migration across tight junctions is mediated by adhesive interactions between epithelial coxsackie and adenovirus receptor and a junctional adhesion molecule-like protein on neutrophils.''; PubMedEurope PMCScholia
Shi X, Niimi S, Ohtani T, Machida S.; ''Characterization of residues and sequences of the carbohydrate recognition domain required for cell surface localization and ligand binding of human lectin-like oxidized LDL receptor.''; PubMedEurope PMCScholia
Popp A, Dehio C, Grunert F, Meyer TF, Gray-Owen SD.; ''Molecular analysis of neisserial Opa protein interactions with the CEA family of receptors: identification of determinants contributing to the differential specificities of binding.''; PubMedEurope PMCScholia
Zhang Z, Morla AO, Vuori K, Bauer JS, Juliano RL, Ruoslahti E.; ''The alpha v beta 1 integrin functions as a fibronectin receptor but does not support fibronectin matrix assembly and cell migration on fibronectin.''; PubMedEurope PMCScholia
Balzar M, Winter MJ, de Boer CJ, Litvinov SV.; ''The biology of the 17-1A antigen (Ep-CAM).''; PubMedEurope PMCScholia
Bogdanovic E, Nguyen VP, Dumont DJ.; ''Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization.''; PubMedEurope PMCScholia
Fraemohs L, Koenen RR, Ostermann G, Heinemann B, Weber C.; ''The functional interaction of the beta 2 integrin lymphocyte function-associated antigen-1 with junctional adhesion molecule-A is mediated by the I domain.''; PubMedEurope PMCScholia
da Costa Martins P, van den Berk N, Ulfman LH, Koenderman L, Hordijk PL, Zwaginga JJ.; ''Platelet-monocyte complexes support monocyte adhesion to endothelium by enhancing secondary tethering and cluster formation.''; PubMedEurope PMCScholia
LDL (low density lipoproteins) are complexes of a single molecule of apoprotein B-100 (apoB-100) non-covalently associated with triacylglycerol, free cholesterol, cholesterol esters, and phospholipids. LDL complexes contain single molecules of apoB-100, but their content of lipids is variable (Chapman et al. 1988; Mateu et al. 1972; Tardieu et al. 1976). High levels of LDL in the blood are strongly correlated with increased risk of atherosclerosis, and recent studies have raised the possibility that this risk is further increased in individuals whose blood LDL population is enriched in high-density (low lipid content) LDL complexes (Rizzo and Berneis 2006). The LDL complex annotated here contains an average lipid composition.
GPVI receptor has little affinity for soluble forms of collagen but binds collagen fibrils. Recent structural models indicate that each GPVI receptor complex could bind up to 3 collagen fibrils (Jung & Moroi 2008). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FceRIgamma complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FceRIgamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation.
Thrombin complexed with thrombomodulin at the endothelial cell surface cleaves the heavy chain of protein C, generating activated protein C and an activation peptide. The activation peptide has no known function.
CD177 is a 58- to 64-kDa glycosylphosphatidylinositol-anchored glycoprotein expressed exclusively by neutrophils, neutrophilic metamyelocytes, and myelocytes, but not by any other blood cells. It has been shown that neutrophil-specific CD177 is a heterophilic binding partner of PECAM-1, constituting a novel pathway that promotes neutrophil transmigration.
Integrin-associated protein (IAP or CD47) is a receptor for thrombospondin family members, a ligand for the transmembrane signaling protein SIRP-alpha and -gamma, and a component of a supramolecular complex containing specific integrins, heterotrimeric G proteins and cholesterol.
Several key IgSF cell adhesion molecules engage integrin and in so doing impact on the multi-step paradigm of leukocyte emigration. The interaction between JAM2 (JAM-B) and Integrin alpha4beta1 (VLA-4) requires prior inding of JAM2 to JAM3 (JAM-C).
MerTK appears to be required for ingestion of apoptotic cells by professional phagocytes such as monocytes/macrophages, retinal pigment epithelial cells and dendritic cells. Mer appears to be able to induce the cytoskeletal remodelling that is required for engulfment during phagocytosis. For instance, a deletion in the MERTK gene was identified as the underlying cause for retinal dystrophy which involves an impairment in the ingestion of shed photoreceptor cell fragments by retinal pigment epithelial cells.
The biological ligands for MerTK are two highly similar vitamin K-dependent proteins, Gas6 and protein S (PS), a negative regulator of blood coagulation. Both proteins are composed an N-terminal region containing multiple post-translationally modified gamma-carboxyglutamic acid residues (Gla). The Gla region possesses the ability to interact in a conformationally specific manner with negatively charged membrane phospholipids, which is thought to mediate the binding of both Gas6 and PS to apoptotic cells. In this way, they are thought to act as recognition bridges between apoptotic cells and the phagocyte cell that ingest them.
CD84 is a homophilic receptor expressed on T cells, B cells, dendritic cells, monocytes, macrophages, eosinophils, mast cells, granulocytes, and platelets. CD84 expression increases following activation of T cells, B cells, and dendritic cells. CD84 homophilic engagement is known to induce platelet stimulation.
The crystal structure of the human CD2-CD58 complex also shows that most of the residues at the interface between these two proteins are charged and form several inter-protein salt bridges.
The presence of CEACAM dimers was shown to lead to an increase in the binding of the integrin alph5 beta1 receptor to its ligand fibronectin, without changing its cell surface levels, resulting in increased adhesion of these cells to fibronectin.
JAM-A plays a key role in leukocyte transmigration and inflammatory extravasation. Transmigration of human leukocytes has been shown to involve heterophilic interactions of JAM-A with its integrin receptor LFA-1.
JAM2 and JAM3 bind each other and are strongly expressed by endothelial cells of high endothelial venules, the predominant site of leukocyte extravasation. JAM2 and JAM3 also bind to the leukocyte integrins VLA-4 and Mac-1 respectively.
CD2, CD48, CD84, CD244 and CD58 have a similar extracellular domain arichitecture consisting of two IgSF domains. CD244 is closely related to CD84 in having a long cytoplasmic tail with tyrosine-based motifs (TxYxxI/V) resembling immunoreceptor tyrosine-based inhibitory motifs (ITIMs). CD2 has a cytoplasmic domain with proline-rich regions which recruit an Src homology 3 (SH3)- containing protein called CD2-associated protein (CD2AP). CD48 is glycosyl-phosphatidyl-inositol (GPI)-anchored to the membrane.
CD244 is known to be activated by binding to CD48 in humans.
Alpha5beta1 integrin was the first integrin shown to bind fibronectin (FN1). Unlike other FN1-binding integrins it is a specialist at this task. In solution FN1 occurs as a dimer. Binding to alpha5beta1 integrin stimulates FN1 self-association; blocking the RGD-cell binding domain of FN1 blocks fibril formation (Fogerty et al. 1990). FN1 binding is believed to induce integrin clustering, which promotes FN1-FN1 interactions. Integrin clustering is mediated by association between integrins and intracellular actin stress fibers (Calderwood et al. 2000). Binding of integrins to each of the monomers in the FN1 dimer pair is thought to trigger a conformational change in FN1 that exposes 'cryptic' FN1 binding sites that allow additional fibronectin dimers to bind without the requirement for pre-association with integrins (Singh et al. 2010). This non-covalent interaction may involve interactions with fibrillin (Ohashi & Erickson 2009). I1-5 functions as a unit that is the primary FN matrix assembly domain (Sottile et al. 1991) but other units are likely to be involved (Singh et al. 2010). Other integrins able to bind FN1 include alphaIIbBeta3, which is highly expressed on platelets where it predominantly binds fibrinogen leading to thrombus formation but also binds FN1 (Savage et al. 1996). Alpha4beta1 mediates cell-cell contacts and cell-matrix contacts through the ligands VCAM-1 and FN1, respectively (Humphries et al. 1995). Integrins alpha3beta1, alpha4beta7, alphaVbeta1, 3 (Johansson et al. 1997), 6 (Busk et al. 1992) and alpha8beta1 (Muller et al. 1995, Farias et al. 2005) are all able to bind FN1.
Tenacious binding of free fibronectin to cells leads to enhanced fibronectin matrix assembly and the formation of a polymerized fibronectin "cocoon" around the cells. This process is enhanced in the presence of CEACAM molecules.
PSGL-1 is expressed as a homodimer of two 120-kDa subunits that binds all four selectins, with the highest affinity for P-selectin, and is known to be constitutively expressed on the surface of platelets and most types of leukocytes. Besides playing a critical role in the inflammatory response by mediating leukocyte-leukocyte and leukocyte-endothelium interactions, PSGL-1 also participates in the hemostatic process by mediating leukocyte-platelet interactions.
F11R (JAM-A) is the most widely expressed member of the family, and has been shown to be expressed on endothelial and epithelial cells, on platelets, and on a number of leukocyte subsets. In endothelial cells, F11R locates to the tight junctions, where it appears to engage in homophilic binding to F11R on adjacent cells, an interaction that is considered to play a critical role in angiogenesis.
Recruitment of monocytic cells to the vessel wall by platelets is mediated via CD11b/CD18 (Mac-1) and platelet JAM-C. In the case of dendritic cells, this interaction leads to their activation and platelet phagocytosis. This process may be of importance for progression of atherosclerotic lesions.
The lectin-like oxidized low density lipoprotein receptor- 1 (Lox-1) mediates the recognition and internalization of oxidatively modified low density lipoprotein. This interaction results in a number of pro-atherogenic cellular responses that probably play a significant role in the pathology of atherosclerosis.
The triggering receptor expressed on myeloid cells 1 (TREM-1) plays an important role in the innate immune response related to severe infections and sepsis. Although the identity and occurrence of the natural TREM-1 ligands are so far unknown, the presence of a ligand for TREM-1 on human platelets has been established. It has been suggested that TREM1 recognizes soluble proteins or cell-surface proteins which are upregulated as a result of inflammation and/or tissue damage and also bacterial LPS (Tessarz & Cerwenka 2008).
Proton-coupled monocarboxylate transporters (MCT) MCT1, MCT3, and MCT4 form heterodimeric complexes with the cell surface glycoprotein CD147 and exhibit tissue-specific polarized distributions that are essential for maintaining lactate and pH homeostasis.
Basigin is a widely distributed cell-surface protein with two immunoglobulin domains and has shown to associate with both the integrins alpha3beta1 and alpha6beta1.
Cyclophilin A (CyPA)1 is an intracellular protein belonging to the immunophilin family and is recognized as the major target for the potent immunosuppressive drug cyclosporin A. CD147 is the natural cell surface receptor for CyPA. It is demonstrated that CD147 is an essential component in the CyPA-initiated signaling cascade that culminates in ERK activation.
Basigin serves as a signaling receptor for extracellular cyclophilins. Its been reported that cyclophilin 60 (Cyp60), a distinct member of the cyclophilin family is involved in the regulation of intracellular transport of basigin. The mechanism of this activity involves interaction of Cyp60 with the proline-containing region within or adjacent to the predicted transmembrane domain basigin. Cyp60 is co-localized with basigin at the plasma membrane suggesting that Cyp60 may function as a chaperone escorting basigin through the secretory pathway.
Stromal fibroblasts secrete multiple matrix metalloproteinases (MMP)1 that can promote tumor cell growth, survival, invasion, angiogenesis, and metastasis. Basigin on the surface of carcinoma cells, stimulates production of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), and MMP-3 (stromelysin). Basigin has been shown to co-immunoprecipitate with caveolin-1. The second Ig domain of Basigin is required for this association, which leads to decreased Besigin self-association on the cell surface. Therefore, caveolin-1 is a negative regulator of CD147 self-association, and its MMP-inducing activity.
Basigin (Bsg) is a highly glycosylated transmembrane protein belonging to the Ig superfamily with two Ig domains. Bsg forms homo-oligomers on the plasma membrane in a cis-dependent manner. The N-terminal Ig-like domain is functionally important in oligomer formation.
Grb7 was initially identified as an EGF receptor binding protein and thereafter many binding partners have been reported. Grb7 interacts with Tie2/Tek in a phosphotyrosine-dependent manner through its SH2 domain.
Tie receptors and their angiopoietin ligands play a critical role in angiogenesis or blood vessel formation. They are considered to control numerous signaling pathways that are involved in diverse cellular processes, such as cell migration, proliferation, survival and reorganization of the actin cytoskeleton.
Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) represents a class of receptor tyrosine kinases (RTKs) that are predominately expressed by vascular endothelial cells. The angiopoietins are a family of growth factors that are largely specific for endothelium and they bind to Tie2/Tek RTKs.
Tie2 signaling initially involves the activation of Tie2 by the interaction of angiopoietin 1. Angiopoietin interacts with the Tie2 receptor with its fibrinogen like domain (FLD). This interaction leads to the dimerization of both the receptor and the ligand, and later initiate the trans-phosphorylation of Tie2.
The p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase) associates with Tie2, most likely at phosphotyrosine 1102. This association leads on to the activation of Akt/PKB, a process linked to cell survival and antiapoptosis, and that may in part account for Tie2's role in vascular growth and maintenance.
Grb14 is also one of the signaling partners of Tie2. The SH2 domain of Grb2 mediates binding to Tie2. It binds residues Y816, Y1108 and Y1113 respectively, in the C-terminal tail region of Tie2/Tek.
Ang4 represents a third protein of the Ang family that binds to the Tie2 receptor. The mouse Ang3 and human Ang4 are interspecies orthologs. Ang4 acts as an activating ligand and induces phosphorylation in Tie2.
Dok-2 is a member of a docking proteins class, termed the DOK family. The DOK family members are characterized by an N-terminal pleckstrin homology (PH) domain followed by a central PTB domain and a proline- and tyrosine-rich C-terminal tail. Dok-2 is recruited to activated Tie2 via its PTB domain, which results in its subsequent tyrosine phosphorylation, thereby establishing binding sites for the small GTPase-activating protein for Ras, p120RasGAP (RasGAP) and the adapter protein Nck. The binding of DOK to the receptor leads to Nck recruitment and subsequent phosphorylation. Binding of Pak to Nck follows. this brings about the Ang-1-dependent phosphorylation of Pak in endothelial cells.
ShcA, an SH2-containing adapter protein, acts as a scaffold for the assembly of signaling proteins involved in the activation of the Ras-MAPK pathway, and potentially other signaling pathways. ShcA is one of the binding partners of endogenous Tie2 receptor on vascular endothelial cells. After Tie2 stimulation by Ang-1 interaction, ShcA associates with Tie2 and becomes tyrosine-phosphorylated. ShcA interacts with the cytoplasmic domain of Tie2 and Y1102 of Tie2 was identified as the primary binding site for the SH2 domain of ShcA. ShcA leads to a reduction of tyrosine phosphorylation of p85 subunit of PI3-kinase and is involved in the inhibition of endothelial cell migration and survival.
The major ligands for Tie2 are Ang1 and Ang2. Ang1 has been considered as the primary activating ligand of Tie2 whereas role of Ang2 remains controversial. Ang2 acts as stimulating in some studies and inhibiting in others. The activity of Ang2 is concentration dependent. Ang2 possesses similar receptor affinity to Ang1 and they both share the same binding site on Tie2. The Ang2 fibrinogen domain is solely responsible for receptor recognition and binding, the coiled-coil motif mediates its oligomerization.
Tie2/Tek provide mitogenic signals to endothelial cells by promoting the association of Grb2 to one of their phosphotyrosines. Grb2 is an adaptor protein that has been linked to activation of Ras and mitogen activated protein kinase (MAPK) cell growth signaling pathways. Grb2 also binds to the Y1102 of the kinase domain of Tie2 with one of its SH2 doamins.
The phosphorylation of two tandem tyrosine residues (Y663 and Y686) within the cytoplasmic domain of PECAM-1 is required for the downstream signalling events observed following PECAM-1 ligation. Both SH2 domains of SHP-1 are required in tandem to bind PECAM-1.
Like SHP-1 and SHP-2, PLC-gamma 1 also interacts with PECAM-1. PLC-gamma 1 binds with both the tyrosine residues (Y663 and Y686). Unlike the N-SH2 domain, the C-SH2 domain on PLC-gamma 1 can only bind phosphotyrosine 663. The engagement of PECAM-1 with PLC-gamma 1 may lead to PLC-gamma 1 activation and subsequent calcium influx.
PECAM-mediated adhesion is complex, because it is capable of binding both to itself (homophilic adhesion) and to non-PECAM ligands (heterophilic adhesion). The trans-homophilic interaction between the two PECAM-1 molecules is mediated by their NH2-terminal membrane distal Ig homology domains 1 and 2 plus the proper spacing formed by the six Ig-homology domains.
PECAM/CD31 is a member of the immunoglobulin superfamily (IgSF) and has been implicated to mediate the adhesion and trans-endothelial migration of T-lymphocytes into the vascular wall, T cell activation and angiogenesis. It has six Ig homology domains within its extracellularly and an ITIM motif within its cytoplasmic region. PECAM-mediated adhesion is complex, because it is capable of binding both to itself (homophilic adhesion) and to non-PECAM ligands (heterophilic adhesion). The trans-homophilic interaction between the two PECAM-1 molecules is mediated by their NH2-terminal membrane distal Ig homology domains 1 and 2 plus the proper spacing formed by the six Ig-homology domains.
PECAM-1 is capable of transmitting information into the cell following its engagement and becomes tyrosine-phosphorylated during the platelet aggregation process. The Src family of tyrosine kinases (more specifically, Src, Lyn, and c-src) has been widely implicated in the phosphorylation of PECAM-1. Conserved tyrosine residues (Tyr663 and Tyr686) within the PECAM-1 cytoplasmic ITIM motif have been shown to become phosphorylated. Tyrosine phosphorylation of PECAM-1 prompts its association with intracellular signal transduction molecules.
PECAM-1 becomes tyrosine-phosphorylated during the platelet aggregation process; the phosphorylation of two tandem tyrosine residues (Y663 and Y686) within the cytoplasmic domain is required for downstream signalling events. Phosphorylation creates docking sites for the protein-tyrosine phosphatase SHP-2. The interaction between SHP-2 and PECAM-1 is dependent upon integrin-mediated platelet/platelet interactions and occurs via the Src homology 2 (SH2) domains of the phosphatase and highly conserved phosphatase-binding motifs encompassing phosphotyrosines 663 and 686 within the cytoplasmic domain of PECAM-1.
Alpha v beta 3 integrin is one of the potential heterophilic ligands of PECAM-1 that is involved in down-regulation of T-cell responses. The heterophilic interaction of alpha v beta 3 integrin on endothelial cells with PEACAM-1 on leukocytes increases the adhesive function of beta integrins on T cells, monocytes, neutrophils and NK cells suggesting that leukocyte PEACAM-1 act as a signaling molecule.
The dimerization of Tie2 leads to autophosphorylation and activation of its kinase domain. There are multiple tyrosine phosphorylation sites in the Tie2 kinase domain. The phosphorylated tyrosine residues provide the interaction site for the SH2 domains of other downstream signaling molecules like PI3K, Grb2, SHP2 etc.
Receptor tyrosine kinase activation and signaling are typically initiated via dimerization of the receptors through homo-oligomeric ligand binding.
Angiopoietin1 may form homotrimers, but in most cases it assembles into higher-order multimers. This oligomerization is mediated by the N-ter coiled coil domain (CCD). The binding of Ang1 oligomers to Tie2 promotes the dimerization of Tie2, which is further assisted by the interaction between the kinase domains of the receptors.
Grb2 binds directly to autophosphorylated Tie2 receptor. GRB2 also contains two SH3 domains, which bring various ligands to the sites of active signaling. One of the SH3 domains on Tie2-bound Grb2 recruits SOS1, an activating nucleotide exchange factor for Ras. This interaction of Sos1 to Grb2 brings Sos1 towards Ras molecules leading to Ras activation. Ras is implicated in the MAP kinase cascade, a pathway in cell growth stimulation, migration and differentiation.
E-selectin is an adhesion molecule on the cell surface of endothelial cells. It participates in the binding of leukocytes to activated blood vascular endothelium during inflammation or metastasis (Haraldsen G et al. 1996). Leucocytes express E-selectin ligand 1 (ESL-1) and P-selectin glycoprotein ligand-1 (PCGL-1) which were identified as the ligands for E-selectin (Graves BJ et al 1994; Asa D et al 1995). E-selectin has been also implicated in mediating tissue-specific homing primitive hematopoietic progenitor cells (HPCs) into bone marrow (BM). PCGL-1, CD43, CD44 were shown to function as E-selectin ligands on human BM cells (Dimitroff CJ et al. 2001; Katayama Y et al. 2003; Merzaban JS et al. 2011).
CD97hc is a multifunctional glycoprotein with a single transmembrane domain, is highly expressed on proliferating cells, and functions as a chaperone for transporters. CD98hc forms disulfide-bonded heterodimers with at least seven different light chains (SLC7A5-11) that serve as amino acid transporters. Covalent cross-linking, mass spectrometric protein identification, and co-immunoprecipitation shows selective CD147 association with CD98hc complex.
Based on in vitro affinity chromatography study, basigin was found to bind to high mannose-carrying cell recognition molecules, such as myelin-associated glycoprotein, L1 and the beta2-subunit of Na+/K+-ATPase.
Basigin (BSG, CD147, EMPRIN) is a glycoprotein expressed on the surface of most tumor cells. It stimulates stromal cells to produce elevated levels of several matrix metalloproteinases (MMP), including interstitial collagenase (MMP1). MMPs have been implicated in several aspects of tumor progression, including invasion through basement membranes and interstitial matrices, angiogenesis, and tumor cell growth. Basigin not only stimulates the production of MMP1 but also forms a complex with MMP1 at the tumor cell surface. This interaction may be important in modifying the tumor cell pericellular matrix to promote invasion.
TNFRSF10D (also known as DcR2 or TRAILR4) inhibits pro-apoptotic signaling by TRAIL (TNFSF10) receptors TNFRSF10A (TRAILR1, DR4) and TNFRSF10B (TRAILR2, DR5). TNFRSF10D has a truncated death domain (DD) but has the motifs involved in oligomerization of TRAIL receptors. While it was initially thought that TNFRSF10D functions as a decoy receptor that competes with TNFRSF10A and TNFRSF10B for ligand binding (Pan et al. 1997), latest studies indicate that it prevents TRAIL signaling by forming heterodimers with TNFRSF10A and TNFRSF10B and thus preventing formation of functional homotrimeric TRAIL ligand:receptor complexes (Neumann et al. 2014).
Macrophage migration inhibitory factor (MIF), one of the first cytokines to be described (George & Vaughan 1962), is an important regulator of innate and adaptive immunity. MIF is an upstream activator of monocytes/macrophages, centrally involved in the pathogenesis of septic shock, arthritis, and other inflammatory conditions (Nishihira 2000, Sanchez-Niño et al. 2013). High-expression Mif alleles are linked to severe rheumatoid arthritis (Morand & Leech 2005). MIF promotes monocyte/macrophage activation and it is required for the optimal expression of TNF-alpha, IL-1, and PGE2 (Calandra & Bucala 1997). MIF-treated macrophages are more phagocytic and better able to destroy intracellular pathogens, such as Leishmania (Rosado & Rodriguez-Sosa 2011). Active MIF is a 37.5 kDa homotrimer.
MIF can bind to CD74 (Leng et al. 2003) and the chemokine receptors CXCR2 and CXCR4 (Bernhagen et al. 2007). Leukocyte recruitment by MIF is mediated by interaction with CXCR2 and CXCR4 (Bernhagen et al. 2007). MIF interaction with CD74 mediates its proproliferative and antiproliferative effects, regulation of B-cell and tumor cell survival, fibrosis and angiogenesis (Starlets et al. 2006). MIF can suppress the immunosuppressive effects of glucocorticoids, inducing a sustained pattern of ERK-1/2 MAP kinase activation (Bach et al. 2009).
MIF is endocytosed to bind the cytosolic protein JAB1 (Schwartz et al. 2012), negatively regulating JAB1-controlled pathways (Kleemann et al. 2000). MIF inhibits JAB1-induced JNK activity, AP-1 activity and JAB1-dependent cell-cycle regulation by stabilizing p27Kip1 protein (Nguyen et al. 2003). Consequently, MIF blocks JAB1-mediated rescue of fibroblasts from growth arrest (Kleemann et al. 2000).
IgA nephropathy (IgAN), the most common glomerulonephritis, is characterized by the deposition of IgA immune complexes in the glomerular mesangium. This is the result of High affinity immunoglobulin alpha and immunoglobulin mu Fc receptor (FCAMR, CD351) binding to IgA (McDonald et al. 2002).
Tetraspanin 7 (TSPAN7) a member of the tetraspanin superfamily associates dynamically with numerous partner proteins in tetraspanin-enriched microdomains (TEMs) of the plasma membrane (Boucheix and Rubinstein, 2001). TSPAN7 promotes filopodia and dendritic spine formation in cultured hippocampal neurons, and is required for spine stability and normal synaptic transmission. Via its C-terminus, TSPAN7 interacts with the PDZ domain of protein interacting with C kinase 1 (PICK1), to regulate PICK1 and GluR2/3 association and AMPA receptor trafficking (Bassani et al. 2012). PICK1 is involved in the internalization and recycling of AMPA receptors (AMPARs) (Perez et al. 2001). In hippocampal neurons, TSPAN7 may regulate AMPA receptor trafficking by limiting PICK1 accessibility to AMPA receptors and suggest an additional mechanism for the functional maturation of glutamatergic synapses, whose impairment is implicated in intellectual disability (Bassani et al. 2012).
The pre-BCR is a heterodimer composed of an immunoglobulin (Ig) heavy chain molecule (IgH) covalently associated with an immunoglobulin light chain-like molecule called the surrogate light chain (SL). The SL consists of two non-covalently associated proteins called lamda-5 (CD179a) and VPREB (CD179b) (Melchers 1993). Pre-BCR signalling promotes the generation of a large pool of precursor cells that can undergo light-chain gene rearrangement (Rickert 2013).
CD99 is a glycoprotein found on the leukocytes surface. It has been variously described as a human thymus leukemia Ag (Levy et al. 1979), a Ewing's sarcoma-specific membrane marker molecule (Hamilton et al. 1988) and a putative adhesion molecule (termed E2) involved in spontaneous rosette formation of T cells with erythrocytes (Aubrit et al. 1989, Bernard et al. 1988). CD99L2 is a paralog of CD99 that directly interacts with CD99 to form a heterodimer via its cytoplasmic domain. This interaction positively regulates CD99L2 trafficking to cell surfaces (Nam et al. 2013).
Red blood cell (RBC) glycophorins are integral membrane proteins that are rich in sialic acids. They carry blood group antigenic determinants and serve as ligands for viruses, bacteria, and parasites. They are used as markers to study normal and pathological differentiation of erythroid tissue. RBC glycophorins include glycophorins A (GPYA) to E and are divided into two groups. GPYA and GPYB carry MN and Ss blood group antigens and may act as receptors for Plasmodium falciparum (Cartron & Rahuel 1992). GPYA and GPYB are recognized by P. falciparum erythrocyte-binding antigen 175 (EBA-175) (Wanaguru et al. 2013) and erythrocyte-binding ligand 1 (EBL-1) (Mayer et al. 2009), respectively. GLYC codes for the Gerbich (Ge) blood group antigens and is a receptor for P. falciparum invasion, recognizing EBA-140 on the surface of merozoites (Maier et al. 2003).
The carcinoembryonic antigen (CEA) gene family, part of the immunoglobulin (Ig) gene superfamily, is a diverse set of highly glycosylated glycoproteins. Two types of membrane anchorage are found in the CEA subgroup of CEACAM proteins. CEACAM1 and CEACAM3 contain a hydrophobic transmembrane domain followed by a cytoplasmic domain, while CEA (also known as CEACAM5) and CEACAM6 are attached to the cell surface via a glycosylphosphatidylinositol (GPI) moiety (Hammarstrom et al. 1999). CEA, CEACAM1, CEACAM3, and CEACAM6 have been shown to serve as receptors for the neisserial phase-variable opacity-associated (Opa) adhesin proteins (Chen & Gotschlich, 1996, Bos et al. 1997, Popp et al. 1999). These adhesin proteins are a major surface component of Neisseria meningitidis and Neisseria gonorrhoeae, and are responsible for bacterial adherence and entry into host cells and interactions with the host immune system. These receptors also bind to DraE adhesin of Escherichia coli (Berger et al. 2004).
Epithelial cell adhesion molecule (EPCAM) is a type I membrane protein expressed in a variety of human epithelial tissues, cancers, and progenitor and stem cells. It consists of an extracellular domain with epidermal growth factor (EGF)-like and thyroglobulin repeat-like domains, a single transmembrane domain, and a short 26-amino acid intracellular domain called EpICD (Balzar et al. 1999). In normal cells EPCAM is predominantly present at the surfaces of intercellular spaces where epithelial cells form very tight junctions. The extracellular domain of EPCAM interacts with a second EPCAM molecule resulting in homotypic cell-cell adhesion (Litvinov et al. 1994, 1997). Formation of EPCAM-mediated adhesions has a negative regulatory effect on adhesions mediated by classic cadherins, which may have strong effects on the differentiation and growth of epithelial cells (Balzar et al. 1999).
The pregnancy-specific glycoproteins (PSGs) are the most abundant trophoblastic proteins in maternal blood during human pregnancy. They are secreted by the syncytiotrophoblast and are detected around day 14 post fertilization. The PSG family belongs to the carcinoembryonic antigen family. There are ten human protein-coding PSG genes (PSG1- PSG9, PSG11) (Thompson et al. 1990). Several studies indicate that PSGs have immunoregulatory, proangiogenic, and anti-platelet functions. PSGs (PSG1) binds to cell surface proteoglycans that have covalently attached glycosaminoglycans (GAGs), specifically to syndecans 1-4 and glypican-1, to induce endothelial tube formation (Lisboa et al. 2011). PSG1 interacts with and activates Transforming growth factor beta 1 (TGFB1) (Blois et al. 2014, Moore & Dveksler 2014). During pregnancy, TGFB1 regulates many processes essential for pregnancy success including trophoblast invasion and proliferation, angiogenesis, extracellular matrix formation and tolerance to the foetal semi-allograft (Jones et al. 2006). TGFB1 also regulates the production of vascular endothelial growth factor (VEGF) and this may contribute to PSG1-induced VEGF-A secretion (Ha et al. 2010). Therefore the pro-angiogenic properties of some PSGs are mediated by two different mechanisms, TGF-beta mediated induction of VEGF-A, and direct interaction of PSGs with GAGs on the surface of endothelial cells.
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DataNodes
alpha3beta1,
alpha6beta1with Surrogate
Light Chainalpha3beta1,
alpha6beta1alpha5beta1:FN1
dimerthe platelet
membranecell recognition
moleculesTransporter Set
(MCT)affecting integrin binding to
fibronectinAnnotated Interactions
alpha3beta1,
alpha6beta1with Surrogate
Light Chainalpha3beta1,
alpha6beta1alpha5beta1:FN1
dimerthe platelet
membranecell recognition
moleculesTransporter Set
(MCT)affecting integrin binding to
fibronectinThe biological ligands for MerTK are two highly similar vitamin K-dependent proteins, Gas6 and protein S (PS), a negative regulator of blood coagulation. Both proteins are composed an N-terminal region containing multiple post-translationally modified gamma-carboxyglutamic acid residues (Gla). The Gla region possesses the ability to interact in a conformationally specific manner with negatively charged membrane phospholipids, which is thought to mediate the binding of both Gas6 and PS to apoptotic cells. In this way, they are thought to act as recognition bridges between apoptotic cells and the phagocyte cell that ingest them.
CD244 is known to be activated by binding to CD48 in humans.
Tenacious binding of free fibronectin to cells leads to enhanced fibronectin matrix assembly and the formation of a polymerized fibronectin "cocoon" around the cells. This process is enhanced in the presence of CEACAM molecules.
Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) represents a class of receptor tyrosine kinases (RTKs) that are predominately expressed by vascular endothelial cells. The angiopoietins are a family of growth factors that are largely specific for endothelium and they bind to Tie2/Tek RTKs.
Tie2 signaling initially involves the activation of Tie2 by the interaction of angiopoietin 1. Angiopoietin interacts with the Tie2 receptor with its fibrinogen like domain (FLD). This interaction leads to the dimerization of both the receptor and the ligand, and later initiate the trans-phosphorylation of Tie2.
ShcA is one of the binding partners of endogenous Tie2 receptor on vascular endothelial cells. After Tie2 stimulation by Ang-1 interaction, ShcA associates with Tie2 and becomes tyrosine-phosphorylated. ShcA interacts with the cytoplasmic domain of Tie2 and Y1102 of Tie2 was identified as the primary binding site for the SH2 domain of ShcA. ShcA leads to a reduction of tyrosine phosphorylation of p85 subunit of PI3-kinase and is involved in the inhibition of endothelial cell migration and survival.
PECAM-mediated adhesion is complex, because it is capable of binding both to itself (homophilic adhesion) and to non-PECAM ligands (heterophilic adhesion). The trans-homophilic interaction between the two PECAM-1 molecules is mediated by their NH2-terminal membrane distal Ig homology domains 1 and 2 plus the proper spacing formed by the six Ig-homology domains.
Angiopoietin1 may form homotrimers, but in most cases it assembles into higher-order multimers. This oligomerization is mediated by the N-ter coiled coil domain (CCD).
The binding of Ang1 oligomers to Tie2 promotes the dimerization of Tie2, which is further assisted by the interaction between the kinase domains of the receptors.
MIF can bind to CD74 (Leng et al. 2003) and the chemokine receptors CXCR2 and CXCR4 (Bernhagen et al. 2007). Leukocyte recruitment by MIF is mediated by interaction with CXCR2 and CXCR4 (Bernhagen et al. 2007). MIF interaction with CD74 mediates its proproliferative and antiproliferative effects, regulation of B-cell and tumor cell survival, fibrosis and angiogenesis (Starlets et al. 2006). MIF can suppress the immunosuppressive effects of glucocorticoids, inducing a sustained pattern of ERK-1/2 MAP kinase activation (Bach et al. 2009).
MIF is endocytosed to bind the cytosolic protein JAB1 (Schwartz et al. 2012), negatively regulating JAB1-controlled pathways (Kleemann et al. 2000). MIF inhibits JAB1-induced JNK activity, AP-1 activity and JAB1-dependent cell-cycle regulation by stabilizing p27Kip1 protein (Nguyen et al. 2003). Consequently, MIF blocks JAB1-mediated rescue of fibroblasts from growth arrest (Kleemann et al. 2000).