Cell surface interactions at the vascular wall (Homo sapiens)

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3, 32, 38, 57, 73...25, 574, 3531, 51, 837820, 54, 61, 67, 8111, 182430, 778026, 6679, 846214, 574828, 29, 46, 71654368865721191536, 378910, 63, 8456, 8416, 27, 877, 946, 695, 23, 57, 882410, 6388247, 5755, 57, 858034, 5745, 59149, 6413, 57, 70, 7253, 84755017, 40, 7453, 847644, 7922, 39, 8233BasiginCD98hc complex SLC7A8SLC3A2 heterodimer SLC7A9SLC3A2 heterodimer cytosolSLC7A9SLC3A2 heterodimer SLC7A10SLC3A2 heterodimer FN1 dimer Selectin SLC7A6SLC3A2 heterodimer Integrin alphaVbeta3 Complex of Tie2Ang-1 SOS-1 bound to Tie2Grb2 JAM-A Homodimer JAM-C homodimer SLC7A5SLC3A2 heterodimer PECAM-1SHP-1 complex Integrin alphaVbeta3PECAM-1 PI3K-catalytic subunit CD58 bound to CD2 FCERIG dimer JAM-B homodimer p85 bound to Tie2 Caveolin-1 bound to Basigin PECAM-1PLC gamma1 complex PECAM-1 bound to CD177 CD47 bound to its ligand Basigin bound to MCTs Integrin alphaXbeta2 FN1 dimer MCT3 homodimer CyP60 complexed with Basigin activated thrombinthrombomodulin pTie2SHC1 complex pTie2Ang-1 VLA-4 JAM-B Sodium/potassium-transporting ATPase beta subunit VLA-4 pTie2Ang-1 Integrin alphaMbeta2JAM3 Integrin alpha5beta1Fibronectin Mannose-carrying cell recognition molecules Basigin homodimer GP VI FceRI gamma dimer Integrin alphaXbeta2AMICA1 BasiginMannose-carrying cell recognition molecules p21 RAS Neutrophil CEACAMs affecting integrin binding to fibronectin JAM-B bound to JAM-C CXADR bound to JAML Basigin-binding integrins Basigin bound to integrins Sodium/potassium-transporting ATPase beta subunit Integrin alphaVbeta3 protein C Basigin bound to CyPA LDL Monocarboxylate Transporter Homodimers Tie2 and Grb14 complex Tie2/Ang1 dimer Integrin alpha3beta1 Integrin alphaLbeta2 Mannose-carrying cell recognition molecules FCERIG dimer OLR1 bound to oxidized LDL TREM-1 bound to its ligand pTie2Ang-1 GP VI FceRI gamma dimer Golgi membraneIntegrin alpha6beta1 Integrin alpha6beta1 Integrin alpha3beta1 SLC7A7SLC3A2 heterodimer pTie2 and SHP2 complex Golgi lumenBasigin-binding integrins CEACAM heterodimer PECAM-1PECAM-1 Complex of Tie2Ang2 PI3K-catalytic subunit SLC7A8SLC3A2 heterodimer PI3K Complex of Tie2Ang-1 MERTK bound to its ligand PI3K-regulatory subunit GPVIFceRI gammaFYNLYN LDL Integrin alphaXbeta2 MCT4 homodimer Integrin alphaMbeta2 pTie2Ang-1 activated thrombin Phosphorylated Tie2 in Tie2/Akt dimer Integrin alpha5beta1 pTie2Ang-1 pTie2Ang-1 GPVIFceRI gammaFYNLYNCollagen type I CD98hc complex p21 RASGTP LFA-1JAM-A PI3K-regulatory subunit Grb2 bound to Tie2 pTie2Ang-1 VLA-4 CD98hc complex P-selectin bound to its ligand MERTK ligands pTie2Ang-1 SLC7A10SLC3A2 heterodimer Integrin alphaLbeta2 Integrin alpha5beta1 SLC7A11SLC3A2 heterodimer p21 RAS pTie2Ang-1 p21 RASGDP GPVIFceRI gammaFYNLYN Basigin bound to CD43 PI3K Tie2Grb7 complex activated protein C BasiginMMP1 SLC7A5SLC3A2 heterodimer Integrin alphaMbeta2 Tie2 and Ang4 complex Grb2 bound to Tie2 SLC7A6SLC3A2 heterodimer PECAM-1SHP-2 complex plasma membraneTie2 and Dok-2 complex p-PECAM1p-PECAM1 SLC7A11SLC3A2 heterodimer MCT1 homodimer PECAM-1SHIP1 complex CD48 bound to CD244 pTie2Ang-1 CD47-binding SIRPs SLC7A7SLC3A2 heterodimer CD84 dimer GRB2-1 PIK3CA ITGAL HRASCEACAM6 ITGAX SLC7A11 ADPLFA-1JAM-AANGPT1 MMP1PROCITGB2 Neutrophil CEACAMs affecting integrin binding to fibronectinITGA5ITGB2 SHC1ANGPT2 11xCbxE-PROS1 PPIAJAM-B bound to JAM-CMAG BSG CHEST 11xCbxE-GAS6FN1 dimerANGPT1 F11R activated thrombinthrombomodulinCD177thrombin heavy chain BSG APOBBSG Basigin bound to CD43PTPN11 Heparan SulphateSPNCD58SIRPG JAM3 VLA-4 JAM-BL1CAM p-5Y,S1119-TEK Tie2 and Dok-2 complexTREM1 GRB2-1Tie2/Ang1 dimerITGAVBSG GRB2-1 Integrin alphaMbeta2SELP TREM1p-5Y,S1119-TEK SLC7A10 ITGA6BasiginMMP1PL NRAS PECAM-1SHIP1 complexPECAM-1PECAM-1Monocarboxylate Transporter Set CD98hc complexITGB1 ANGPT4 SLC7A5 ATP1B2 ANGPT4thrombin light chain CXADRCD48BSGGTPFN1INPP5D CXADR bound to JAMLGDPCD177 MERTK ligandsKRASComplex of Tie2Ang-1SELE PIK3R2 NRAS GPVIFceRI gammaFYNLYNSIRPA HRASSELPLG ANGPT1 CD47-binding SIRPsBasigin-binding integrinspTie2SHC1 complexCD48 SLC7A6 PROCComplex of Tie2Ang2TREM-1 bound to its ligandSLC7A5 PTPN6p-5Y,S1119-TEK L1CAM ITGAX SLC7A7 SELL p-Y663,Y686-PECAM1CD244 CHOL PECAM1CAV1 JAM-B homodimerITGB3 PROCITGB2 Caveolin-1 bound to BasiginBSGGRB7 SLC7A6 activated protein CSPN PTPN6 BasiginMannose-carrying cell recognition moleculesITGB1 p-Y663,Y686-PECAM1SLC16A3JAM3 SLC3A2 MMP1ATP1B1 CD58ADPPECAM1p85 bound to Tie2Integrin alphaXbeta2Tie2 and Grb14 complexPlatelet Factor 4GRB14 ITGB3 TEK Ca2+ pTie2Ang-1ITGAM JAM2GPVIFceRI gammaFYNLYNCollagen type IATP1B3 SLC7A9 ANGPT1 SLC7A10 ANGPT1 GDP CEACAM8 ANGPT1 OLR1CEACAM heterodimerPECAM1ITGAVCD84 TEK CD47 CXADR FCER1G THBDITGAM ANGPT1 p-PECAM1p-PECAM1ITGB1 Tie2 and Ang4 complexPTPN11 CyP60 complexed with BasiginSrc family tyrosine kinases PECAM-1PLC gamma1 complexJAM-A HomodimerPPIL2 p-5Y,S1119-TEK INPP5DCollagen type I fibrilITGB1 CD2Tie2Grb7 complexBasiginCD98hc complexIntegrin alphaLbeta2 FYNPLCG1p-5Y,S1119-TEK ATP1B2 PIK3CB FCER1G PLCG1LYNBSG Mannose-carrying cell recognition moleculesprotein CANGPT1 GP6 p-5Y,S1119-TEK FYNOLR1 bound to oxidized LDLBSG ATPANGPT1 SHC1 PECAM1SLC7A11 DOK2 JAM2MERTK bound to its ligandITGB1 p21 RASGDPp21 RASGTPPL SLC7A8 ITGA4ITGB1 TAGs ATP1B1 CHOL pTie2 and SHP2 complexMERTKBSG SelectinATPTEK ITGA3PI3KITGA3Ca2+ TEK Integrin alphaVbeta3PECAM-1PIK3CB APOBPIK3R2 ANGPT1 ITGA4PIK3CA BSG CD2 SOS1 ITGB2 F11RPPIL2JAM2 SLC16A8 SLC16A1 MERTK SOS1p-Y663,Y686-PECAM1P-selectin bound to its ligandITGB2 BSG GP6 JAM3 ITGA5PPIA 8xCbxE-3D-PROCOLR1 p-5Y,S1119-TEK Basigin bound to MCTsIntegrin alphaMbeta2JAM3SPNAMICA1Basigin homodimerIntegrin alpha5beta1FibronectinTEKp-Y663,Y686-PECAM1SLC7A8 Mn2+ Integrin alphaVbeta3CD84PIK3R1 CD58 bound to CD2Ligand to TREM-1 on the platelet membraneSOS-1 bound to Tie2Grb2p-Y663,Y686-PECAM1CD48 bound to CD244ANGPT1CD84 dimerp-5Y,S1119-TEK ITGB2 p-5Y,S1119-TEK ANGPT1 ANGPT2ESAM SLC3A2 8xCbxE-3D-PROCSLC7A7 Mn2+VLA-4ATP1B3 PECAM-1SHP-1 complexLYNTAGs BSG PECAM-1SHP-2 complexPECAM-1 bound to CD177F11R CAV1FN1JAM2 Basigin bound to integrinsCEACAM1 p-5Y,S1119-TEK GTP JAM3 JAM-C homodimerPTPN11SLC7A9 Integrin alpha5beta1CD244DOK2GRB7SELPLGMAG AMICA1 LDLITGAL CD47ANGPT1 GRB14Integrin alphaXbeta2AMICA1JAM3Basigin bound to CyPAPhosphorylated Tie2 in Tie2/Akt dimerp-Y663,Y686-PECAM1CHEST PIK3R1 KRASITGA6CD47 bound to its ligandGrb2 bound to Tie26, 41604, 6, 414, 6, 41394260526, 41394, 6, 416, 41, 5812356, 41, 586522


Description

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.

Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=202733</div>

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  86. 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.''; PubMed Europe PMC Scholia
  87. 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.''; PubMed Europe PMC Scholia
  88. Becker BF, Heindl B, Kupatt C, Zahler S.; ''Endothelial function and hemostasis.''; PubMed Europe PMC Scholia
  89. 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.''; PubMed Europe PMC Scholia
  90. 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.''; PubMed Europe PMC Scholia
  91. Mandicourt G, Iden S, Ebnet K, Aurrand-Lions M, Imhof BA.; ''JAM-C regulates tight junctions and integrin-mediated cell adhesion and migration.''; PubMed Europe PMC Scholia
  92. 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.''; PubMed Europe PMC Scholia
  93. 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.''; PubMed Europe PMC Scholia
  94. 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.''; PubMed Europe PMC Scholia
  95. 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.''; PubMed Europe PMC Scholia
  96. 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.''; PubMed Europe PMC Scholia
  97. 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.''; PubMed Europe PMC Scholia
  98. 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.''; PubMed Europe PMC Scholia
  99. Schober A, Weber C.; ''Mechanisms of monocyte recruitment in vascular repair after injury.''; PubMed Europe PMC Scholia
  100. Cunningham SA, Rodriguez JM, Arrate MP, Tran TM, Brock TA.; ''JAM2 interacts with alpha4beta1. Facilitation by JAM3.''; PubMed Europe PMC Scholia
  101. 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.''; PubMed Europe PMC Scholia
  102. Bos MP, Grunert F, Belland RJ.; ''Differential recognition of members of the carcinoembryonic antigen family by Opa variants of Neisseria gonorrhoeae.''; PubMed Europe PMC Scholia
  103. 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.''; PubMed Europe PMC Scholia
  104. 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.''; PubMed Europe PMC Scholia
  105. 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.''; PubMed Europe PMC Scholia
  106. 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.''; PubMed Europe PMC Scholia
  107. Balzar M, Winter MJ, de Boer CJ, Litvinov SV.; ''The biology of the 17-1A antigen (Ep-CAM).''; PubMed Europe PMC Scholia
  108. Bogdanovic E, Nguyen VP, Dumont DJ.; ''Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization.''; PubMed Europe PMC Scholia
  109. 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.''; PubMed Europe PMC Scholia
  110. 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.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
112591view15:56, 9 October 2020ReactomeTeamReactome version 73
101507view11:37, 1 November 2018ReactomeTeamreactome version 66
101043view21:18, 31 October 2018ReactomeTeamreactome version 65
100574view19:51, 31 October 2018ReactomeTeamreactome version 64
100123view16:37, 31 October 2018ReactomeTeamreactome version 63
99673view15:07, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99268view12:45, 31 October 2018ReactomeTeamreactome version 62
94057view13:54, 16 August 2017ReactomeTeamreactome version 61
93737view13:25, 16 August 2017ReactomeTeamreactome version 61
93686view11:31, 9 August 2017ReactomeTeamreactome version 61
87157view19:14, 18 July 2016MkutmonOntology Term : 'hemostasis pathway' added !
86809view09:27, 11 July 2016ReactomeTeamreactome version 56
83824view13:10, 13 December 2015EgonwMarked heparan sulfate (HS) as a metabolite.
83200view10:21, 18 November 2015ReactomeTeamVersion54
81579view13:07, 21 August 2015ReactomeTeamVersion53
77039view08:33, 17 July 2014ReactomeTeamFixed remaining interactions
76744view12:10, 16 July 2014ReactomeTeamFixed remaining interactions
76069view10:13, 11 June 2014ReactomeTeamRe-fixing comment source
75779view11:29, 10 June 2014ReactomeTeamReactome 48 Update
75129view14:07, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74859view15:22, 2 May 2014EgonwMarked a metabolite as a DataNode type="Metabolite"...
74776view08:51, 30 April 2014ReactomeTeamReactome46
42017view21:50, 4 March 2011MaintBotAutomatic update
39820view05:51, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
11xCbxE-GAS6ProteinQ14393 (Uniprot-TrEMBL)
11xCbxE-PROS1 ProteinP07225 (Uniprot-TrEMBL)
8xCbxE-3D-PROCProteinP04070 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AMICA1 ProteinQ86YT9 (Uniprot-TrEMBL)
AMICA1ProteinQ86YT9 (Uniprot-TrEMBL)
ANGPT1 ProteinQ15389 (Uniprot-TrEMBL)
ANGPT1ProteinQ15389 (Uniprot-TrEMBL)
ANGPT2 ProteinO15123 (Uniprot-TrEMBL)
ANGPT2ProteinO15123 (Uniprot-TrEMBL)
ANGPT4 ProteinQ9Y264 (Uniprot-TrEMBL)
ANGPT4ProteinQ9Y264 (Uniprot-TrEMBL)
APOBProteinP04114 (Uniprot-TrEMBL)
ATP1B1 ProteinP05026 (Uniprot-TrEMBL)
ATP1B2 ProteinP14415 (Uniprot-TrEMBL)
ATP1B3 ProteinP54709 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BSG ProteinP35613 (Uniprot-TrEMBL)
BSGProteinP35613 (Uniprot-TrEMBL)
Basigin CD98hc complexComplexREACT_17413 (Reactome)
Basigin MMP1ComplexREACT_17528 (Reactome)
Basigin Mannose-carrying cell recognition moleculesComplexREACT_18084 (Reactome)
Basigin bound to CD43ComplexREACT_18170 (Reactome)
Basigin bound to CyPAComplexREACT_12714 (Reactome)
Basigin bound to MCTsComplexREACT_15052 (Reactome)
Basigin bound to integrinsComplexREACT_14081 (Reactome)
Basigin homodimerComplexREACT_13277 (Reactome)
Basigin-binding integrinsComplexREACT_14484 (Reactome)
CAV1 ProteinQ03135 (Uniprot-TrEMBL)
CAV1ProteinQ03135 (Uniprot-TrEMBL)
CD177 ProteinQ8N6Q3 (Uniprot-TrEMBL)
CD177ProteinQ8N6Q3 (Uniprot-TrEMBL)
CD2 ProteinP06729 (Uniprot-TrEMBL)
CD244 ProteinQ9BZW8 (Uniprot-TrEMBL)
CD244ProteinQ9BZW8 (Uniprot-TrEMBL)
CD2ProteinP06729 (Uniprot-TrEMBL)
CD47 ProteinQ08722 (Uniprot-TrEMBL)
CD47 bound to its ligandComplexREACT_12217 (Reactome)
CD47-binding SIRPsProteinREACT_12311 (Reactome)
CD47ProteinQ08722 (Uniprot-TrEMBL)
CD48 ProteinP09326 (Uniprot-TrEMBL)
CD48 bound to CD244ComplexREACT_12345 (Reactome)
CD48ProteinP09326 (Uniprot-TrEMBL)
CD58 bound to CD2ComplexREACT_12230 (Reactome)
CD58ProteinP19256 (Uniprot-TrEMBL)
CD84 ProteinQ9UIB8 (Uniprot-TrEMBL)
CD84 dimerComplexREACT_12135 (Reactome)
CD84ProteinQ9UIB8 (Uniprot-TrEMBL)
CD98hc complexComplexREACT_18154 (Reactome)
CEACAM heterodimerComplexREACT_12134 (Reactome)
CEACAM1 ProteinP13688 (Uniprot-TrEMBL)
CEACAM6 ProteinP40199 (Uniprot-TrEMBL)
CEACAM8 ProteinP31997 (Uniprot-TrEMBL)
CHEST MetaboliteCHEBI:17002 (ChEBI)
CHOL MetaboliteCHEBI:16113 (ChEBI)
CXADR ProteinP78310 (Uniprot-TrEMBL)
CXADR bound to JAMLComplexREACT_11619 (Reactome)
CXADRProteinP78310 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Caveolin-1 bound to BasiginComplexREACT_13130 (Reactome)
Collagen type I fibrilREACT_150867 (Reactome)
Complex of Tie2 Ang-1ComplexREACT_12688 (Reactome)
Complex of Tie2 Ang2ComplexREACT_12895 (Reactome)
CyP60 complexed with BasiginComplexREACT_12835 (Reactome)
DOK2 ProteinO60496 (Uniprot-TrEMBL)
DOK2ProteinO60496 (Uniprot-TrEMBL)
ESAM ProteinQ96AP7 (Uniprot-TrEMBL)
F11R ProteinQ9Y624 (Uniprot-TrEMBL)
F11RProteinQ9Y624 (Uniprot-TrEMBL)
FCER1G ProteinP30273 (Uniprot-TrEMBL)
FN1 dimerComplexREACT_14040 (Reactome)
FN1ProteinP02751 (Uniprot-TrEMBL)
FYNProteinP06241 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GP6 ProteinQ9HCN6 (Uniprot-TrEMBL)
GPVI

FceRI gamma FYN LYN

Collagen type I		ComplexREACT_20373 (Reactome)
GPVI

FceRI gamma FYN

LYN		ComplexREACT_20322 (Reactome)
GRB14 ProteinQ14449 (Uniprot-TrEMBL)
GRB14ProteinQ14449 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GRB7 ProteinQ14451 (Uniprot-TrEMBL)
GRB7ProteinQ14451 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Grb2 bound to Tie2ComplexREACT_12659 (Reactome)
HRASProteinP01112 (Uniprot-TrEMBL)
Heparan SulphateCHEBI:28815 (ChEBI)
INPP5D ProteinQ92835 (Uniprot-TrEMBL)
INPP5DProteinQ92835 (Uniprot-TrEMBL)
ITGA3ProteinP26006 (Uniprot-TrEMBL)
ITGA4ProteinP13612 (Uniprot-TrEMBL)
ITGA5ProteinP08648 (Uniprot-TrEMBL)
ITGA6ProteinP23229 (Uniprot-TrEMBL)
ITGAL ProteinP20701 (Uniprot-TrEMBL)
ITGAM ProteinP11215 (Uniprot-TrEMBL)
ITGAVProteinP06756 (Uniprot-TrEMBL)
ITGAX ProteinP20702 (Uniprot-TrEMBL)
ITGB1 ProteinP05556 (Uniprot-TrEMBL)
ITGB2 ProteinP05107 (Uniprot-TrEMBL)
ITGB3 ProteinP05106 (Uniprot-TrEMBL)
Integrin alpha5beta1 FibronectinComplexREACT_12353 (Reactome)
Integrin alpha5beta1ComplexREACT_12335 (Reactome)
Integrin alphaLbeta2 ComplexREACT_11837 (Reactome)
Integrin alphaMbeta2 JAM3ComplexREACT_12228 (Reactome)
Integrin alphaMbeta2ComplexREACT_12291 (Reactome)
Integrin alphaVbeta3 PECAM-1ComplexREACT_13361 (Reactome)
Integrin alphaVbeta3ComplexREACT_13287 (Reactome)
Integrin alphaXbeta2 AMICA1ComplexREACT_12224 (Reactome)
Integrin alphaXbeta2ComplexREACT_12091 (Reactome)
JAM-A HomodimerComplexREACT_12319 (Reactome)
JAM-B bound to JAM-CComplexREACT_12255 (Reactome)
JAM-B homodimerComplexREACT_12209 (Reactome)
JAM-C homodimerComplexREACT_12100 (Reactome)
JAM2 ProteinP57087 (Uniprot-TrEMBL)
JAM2ProteinP57087 (Uniprot-TrEMBL)
JAM3 ProteinQ9BX67 (Uniprot-TrEMBL)
JAM3ProteinQ9BX67 (Uniprot-TrEMBL)
KRASProteinP01116 (Uniprot-TrEMBL)
L1CAM ProteinP32004 (Uniprot-TrEMBL)
LDLComplexREACT_7774 (Reactome) 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.
LFA-1 JAM-AComplexREACT_12182 (Reactome)
LYNProteinP07948 (Uniprot-TrEMBL)
Ligand to TREM-1 on the platelet membraneREACT_12176 (Reactome)
MAG ProteinP20916 (Uniprot-TrEMBL)
MERTK ProteinQ12866 (Uniprot-TrEMBL)
MERTK bound to its ligandComplexREACT_12164 (Reactome)
MERTK ligandsProteinREACT_12235 (Reactome)
MERTKProteinQ12866 (Uniprot-TrEMBL)
MMP1ProteinP03956 (Uniprot-TrEMBL)
Mannose-carrying cell recognition moleculesComplexREACT_18192 (Reactome)
Mn2+ MetaboliteCHEBI:18291 (ChEBI)
Mn2+MetaboliteCHEBI:18291 (ChEBI)
Monocarboxylate Transporter Set ProteinREACT_17955 (Reactome)
NRAS ProteinP01111 (Uniprot-TrEMBL)
Neutrophil CEACAMs affecting integrin binding to fibronectinProteinREACT_12292 (Reactome)
OLR1 ProteinP78380 (Uniprot-TrEMBL)
OLR1 bound to oxidized LDLComplexREACT_12181 (Reactome)
OLR1ProteinP78380 (Uniprot-TrEMBL)
P-selectin bound to its ligandComplexREACT_12193 (Reactome)
PECAM-1 PECAM-1ComplexREACT_13059 (Reactome)
PECAM-1 PLC gamma1 complexComplexREACT_13045 (Reactome)
PECAM-1 SHIP1 complexComplexREACT_13027 (Reactome)
PECAM-1 SHP-1 complexComplexREACT_13228 (Reactome)
PECAM-1 SHP-2 complexComplexREACT_13041 (Reactome)
PECAM-1 bound to CD177ComplexREACT_12173 (Reactome)
PECAM1ProteinP16284 (Uniprot-TrEMBL)
PI3KComplexREACT_4240 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PL MetaboliteCHEBI:16247 (ChEBI)
PLCG1ProteinP19174 (Uniprot-TrEMBL)
PPIA ProteinP62937 (Uniprot-TrEMBL)
PPIAProteinP62937 (Uniprot-TrEMBL)
PPIL2 ProteinQ13356 (Uniprot-TrEMBL)
PPIL2ProteinQ13356 (Uniprot-TrEMBL)
PROCProteinP04070 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6ProteinP29350 (Uniprot-TrEMBL)
Phosphorylated Tie2 in Tie2/Akt dimerComplexREACT_13046 (Reactome)
Platelet Factor 4REACT_12205 (Reactome)
SELE ProteinP16581 (Uniprot-TrEMBL)
SELL ProteinP14151 (Uniprot-TrEMBL)
SELP ProteinP16109 (Uniprot-TrEMBL)
SELPLG ProteinQ14242 (Uniprot-TrEMBL)
SELPLGProteinQ14242 (Uniprot-TrEMBL)
SHC1 ProteinP29353 (Uniprot-TrEMBL)
SHC1ProteinP29353 (Uniprot-TrEMBL)
SIRPA ProteinP78324 (Uniprot-TrEMBL)
SIRPG ProteinQ9P1W8 (Uniprot-TrEMBL)
SLC16A1 ProteinP53985 (Uniprot-TrEMBL)
SLC16A3ProteinO15427 (Uniprot-TrEMBL)
SLC16A8 ProteinO95907 (Uniprot-TrEMBL)
SLC3A2 ProteinP08195 (Uniprot-TrEMBL)
SLC7A10 ProteinQ9NS82 (Uniprot-TrEMBL)
SLC7A11 ProteinQ9UPY5 (Uniprot-TrEMBL)
SLC7A5 ProteinQ01650 (Uniprot-TrEMBL)
SLC7A6 ProteinQ92536 (Uniprot-TrEMBL)
SLC7A7 ProteinQ9UM01 (Uniprot-TrEMBL)
SLC7A8 ProteinQ9UHI5 (Uniprot-TrEMBL)
SLC7A9 ProteinP82251 (Uniprot-TrEMBL)
SOS-1 bound to Tie2 Grb2ComplexREACT_13320 (Reactome)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SOS1ProteinQ07889 (Uniprot-TrEMBL)
SPN ProteinP16150 (Uniprot-TrEMBL)
SPNProteinP16150 (Uniprot-TrEMBL)
SelectinProteinREACT_12297 (Reactome)
Src family tyrosine kinases REACT_13328 (Reactome)
TAGs MetaboliteCHEBI:17855 (ChEBI)
TEK ProteinQ02763 (Uniprot-TrEMBL)
TEKProteinQ02763 (Uniprot-TrEMBL)
THBDProteinP07204 (Uniprot-TrEMBL)
TREM-1 bound to its ligandComplexREACT_12367 (Reactome)
TREM1 ProteinQ9NP99 (Uniprot-TrEMBL)
TREM1ProteinQ9NP99 (Uniprot-TrEMBL)
Tie2 Grb7 complexComplexREACT_18058 (Reactome)
Tie2 and Ang4 complexComplexREACT_12703 (Reactome)
Tie2 and Dok-2 complexComplexREACT_13019 (Reactome)
Tie2 and Grb14 complexComplexREACT_18185 (Reactome)
Tie2/Ang1 dimerComplexREACT_13336 (Reactome)
VLA-4 JAM-BComplexREACT_12179 (Reactome)
VLA-4ComplexREACT_11798 (Reactome)
activated protein CComplexREACT_2599 (Reactome)
activated thrombin thrombomodulinComplexREACT_5904 (Reactome)
p-5Y,S1119-TEK ProteinQ02763 (Uniprot-TrEMBL)
p-PECAM1 p-PECAM1ComplexREACT_12801 (Reactome)
p-Y663,Y686-PECAM1ProteinP16284 (Uniprot-TrEMBL)
p21 RAS GDPComplexREACT_2657 (Reactome)
p21 RAS GTPComplexREACT_4782 (Reactome)
p85 bound to Tie2ComplexREACT_13298 (Reactome)
pTie2 Ang-1ComplexREACT_13342 (Reactome)
pTie2 SHC1 complexComplexREACT_12988 (Reactome)
pTie2 and SHP2 complexComplexREACT_17975 (Reactome)
protein CComplexREACT_4912 (Reactome)
thrombin heavy chain ProteinP00734 (Uniprot-TrEMBL)
thrombin light chain ProteinP00734 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_12408 (Reactome)
ADPArrowREACT_12496 (Reactome)
AMICA1REACT_11154 (Reactome)
AMICA1REACT_12064 (Reactome)
ANGPT1REACT_12523 (Reactome)
ANGPT2REACT_12547 (Reactome)
ANGPT4REACT_12598 (Reactome)
ATPREACT_12408 (Reactome)
ATPREACT_12496 (Reactome)
BSGREACT_12497 (Reactome)
BSGREACT_12550 (Reactome)
BSGREACT_12637 (Reactome)
BSGREACT_13430 (Reactome)
BSGREACT_16882 (Reactome)
BSGREACT_16931 (Reactome)
BSGREACT_16941 (Reactome)
BSGREACT_16975 (Reactome)
BSGREACT_16988 (Reactome)
Basigin-binding integrinsREACT_13430 (Reactome)
CAV1REACT_12637 (Reactome)
CD177REACT_12006 (Reactome)
CD244REACT_12018 (Reactome)
CD2REACT_12031 (Reactome)
CD47-binding SIRPsREACT_12068 (Reactome)
CD47REACT_12068 (Reactome)
CD48REACT_12018 (Reactome)
CD58REACT_12031 (Reactome)
CD98hc complexREACT_16988 (Reactome)
CXADRREACT_11154 (Reactome)
Collagen type I fibrilREACT_1088 (Reactome)
Complex of Tie2 Ang-1REACT_12496 (Reactome)
DOK2REACT_12575 (Reactome)
F11RREACT_12042 (Reactome)
FN1 dimerREACT_12043 (Reactome)
GDPArrowREACT_12516 (Reactome)
GPVI

FceRI gamma FYN

LYN		REACT_1088 (Reactome)
GRB14REACT_16885 (Reactome)
GRB2-1REACT_12511 (Reactome)
GRB7REACT_16914 (Reactome)
GTPREACT_12516 (Reactome)
Grb2 bound to Tie2REACT_12504 (Reactome)
Heparan SulphateArrowREACT_12497 (Reactome)
INPP5DREACT_12476 (Reactome)
Integrin alpha5beta1REACT_12043 (Reactome)
Integrin alphaLbeta2 REACT_12042 (Reactome)
Integrin alphaMbeta2REACT_12035 (Reactome)
Integrin alphaVbeta3REACT_12468 (Reactome)
Integrin alphaXbeta2REACT_12064 (Reactome)
JAM2REACT_12040 (Reactome)
JAM2REACT_12053 (Reactome)
JAM3REACT_12035 (Reactome)
JAM3REACT_12053 (Reactome)
LDLREACT_12039 (Reactome)
Ligand to TREM-1 on the platelet membraneREACT_12047 (Reactome)
MERTK ligandsREACT_12060 (Reactome)
MERTKREACT_12060 (Reactome)
MMP1REACT_16941 (Reactome)
Mannose-carrying cell recognition moleculesREACT_16975 (Reactome)
Mn2+REACT_12043 (Reactome)
Monocarboxylate Transporter Set REACT_16882 (Reactome)
OLR1REACT_12039 (Reactome)
PECAM-1 PECAM-1REACT_12408 (Reactome)
PECAM1REACT_12006 (Reactome)
PECAM1REACT_12468 (Reactome)
PI3KREACT_12475 (Reactome)
PLCG1REACT_12540 (Reactome)
PPIAREACT_12497 (Reactome)
PPIL2REACT_12550 (Reactome)
PROCArrowREACT_374 (Reactome)
PTPN11REACT_12509 (Reactome)
PTPN11REACT_16906 (Reactome)
PTPN6REACT_12552 (Reactome)
Phosphorylated Tie2 in Tie2/Akt dimerArrowREACT_12496 (Reactome)
Platelet Factor 4ArrowREACT_374 (Reactome)
REACT_1088 (Reactome) 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.
REACT_11154 (Reactome) JAM members, such as JAML, bind coxsackie and adenovirus receptor (CXADR) on epithelial and endothelial cells.
REACT_11994 (Reactome) Apart from its well-established interaction with VLA-4, JAM-B is also known to homodimerize.
REACT_11999 (Reactome) 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, JAM-A locates to the tight junctions, where it appears to engage in homophilic binding to JAM-A on adjacent cells, an interaction that is considered to play a critical role in angiogenesis.
REACT_12006 (Reactome) 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.
REACT_12018 (Reactome) 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.

REACT_12027 (Reactome) 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.
REACT_12029 (Reactome) JAM-C has been detected in epithelial-cell desmosomes. JAM-C homodimers are prominently located in endothelial-cell tight junctions.
REACT_12031 (Reactome) 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.
REACT_12035 (Reactome) 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.
REACT_12039 (Reactome) 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.
REACT_12040 (Reactome) Several key IgSF cell adhesion molecules engage integrin and in so doing impact on the multi-step paradigm of leukocyte emigration. The interaction between JAM-B and VLA-4 is facilitated by prior engagement of JAM-B with JAM-C.
REACT_12042 (Reactome) 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.
REACT_12043 (Reactome) 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 and alphaVbeta1, 3 and 6 are all reported to bind FN1 (Johansson et al. 1997)


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.
REACT_12047 (Reactome) 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).
REACT_12053 (Reactome) JAM-B and -C bind each other and are strongly expressed by endothelial cells of high endothelial venules, the predominant site of leukocyte extravasation. JAM-B and -C also bind to the leukocyte integrins VLA-4 and Mac-1 respectively.
REACT_12060 (Reactome) 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.

REACT_12064 (Reactome) Although JAM-C is better known for its interaction with MAC-1, an interaction with CD11c/CD18 (known as alpha X beta 2), has also been described.
REACT_12068 (Reactome) 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.
REACT_12073 (Reactome) 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.
REACT_12081 (Reactome) 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.
REACT_12408 (Reactome) 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.
REACT_12409 (Reactome) 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.
REACT_12419 (Reactome) 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.
REACT_12431 (Reactome) 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.
REACT_12468 (Reactome) 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.
REACT_12475 (Reactome) 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.
REACT_12476 (Reactome) 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.
REACT_12496 (Reactome) 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.
REACT_12497 (Reactome) 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.
REACT_12504 (Reactome) 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.
REACT_12509 (Reactome) 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.
REACT_12511 (Reactome) 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.
REACT_12516 (Reactome) Sos-1 bound to Grb2:Tie2 complex promotes the exchange of inactive Ras-GDP to active Ras-GTP.
REACT_12523 (Reactome) 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.
REACT_12540 (Reactome) 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.
REACT_12547 (Reactome) 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.
REACT_12550 (Reactome) 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.
REACT_12552 (Reactome) 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.
REACT_12575 (Reactome) 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.
REACT_12593 (Reactome) 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.

REACT_12598 (Reactome) 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.
REACT_12637 (Reactome) 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.
REACT_13430 (Reactome) Basigin is a widely distributed cell-surface protein with two immunoglobulin domains and has shown to associate with both the integrins alpha3beta1 and alpha6beta1.
REACT_16882 (Reactome) 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.
REACT_16885 (Reactome) 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.
REACT_16906 (Reactome) Shp2 interact with Tyr816 in the juxtamembrane region and Tyr1108 and Tyr1113, respectively, in the C-terminal tail region of Tie2/Tek.
REACT_16914 (Reactome) 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.
REACT_16931 (Reactome) CD43, a major leukocyte cell surface sialoglycoprotein, interacts directly with Basigin.
REACT_16941 (Reactome) Basigin expressed on the surface of most tumor cells, stimulates stromal cells to produce elevated levels of several matrix metalloproteinases (MMP), including interstitial collagenase (MMP-1). 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 MMP-1 but also forms a complex with MMP-1 at the tumor cell surface and this interaction may be important in modifying the tumor cell pericellular matrix to promote invasion.
REACT_16975 (Reactome) 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.
REACT_16988 (Reactome) 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.
REACT_374 (Reactome) 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.
SELPLGREACT_12081 (Reactome)
SHC1REACT_12409 (Reactome)
SOS-1 bound to Tie2 Grb2REACT_12516 (Reactome)
SOS1REACT_12504 (Reactome)
SPNREACT_16931 (Reactome)
SelectinREACT_12081 (Reactome)
Src family tyrosine kinases REACT_12408 (Reactome)
TEKREACT_12523 (Reactome)
TEKREACT_12547 (Reactome)
TEKREACT_12598 (Reactome)
TREM1REACT_12047 (Reactome)
Tie2/Ang1 dimerREACT_12496 (Reactome)
VLA-4REACT_12040 (Reactome)
activated protein CArrowREACT_374 (Reactome)
activated thrombin thrombomodulinREACT_374 (Reactome)
p-PECAM1 p-PECAM1ArrowREACT_12408 (Reactome)
p-Y663,Y686-PECAM1REACT_12476 (Reactome)
p-Y663,Y686-PECAM1REACT_12509 (Reactome)
p-Y663,Y686-PECAM1REACT_12540 (Reactome)
p-Y663,Y686-PECAM1REACT_12552 (Reactome)
p21 RAS GDPREACT_12516 (Reactome)
p21 RAS GTPArrowREACT_12516 (Reactome)
pTie2 Ang-1REACT_12409 (Reactome)
pTie2 Ang-1REACT_12475 (Reactome)
pTie2 Ang-1REACT_12511 (Reactome)
pTie2 Ang-1REACT_12575 (Reactome)
pTie2 Ang-1REACT_16885 (Reactome)
pTie2 Ang-1REACT_16906 (Reactome)
pTie2 Ang-1REACT_16914 (Reactome)

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