Cell surface interactions at the vascular wall (Homo sapiens)
From WikiPathways
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.
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- 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
- 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
- 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
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- 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
- 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
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History
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External references
DataNodes
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 2xANGPT1:TEK | Arrow | R-HSA-210881 (Reactome)  | ||
| 2xANGPT1:TEK | R-HSA-210872 (Reactome) | |||
| ADP | Arrow | R-HSA-210291 (Reactome) | ||
| ADP | Arrow | R-HSA-210872 (Reactome) | ||
| AMICA1 | R-HSA-199093 (Reactome) | |||
| ANGPT1:TEK | Arrow | R-HSA-204779 (Reactome) | ||
| ANGPT1:TEK | R-HSA-210881 (Reactome) | |||
| ANGPT1:TEK | mim-catalysis | R-HSA-210872 (Reactome) | ||
| ANGPT1:p-5Y,S119-TEK:SHC1 | Arrow | R-HSA-204861 (Reactome) | ||
| ANGPT1:p-5Y,S119-TEK | R-HSA-204773 (Reactome) | |||
| ANGPT1:p-5Y,S119-TEK | R-HSA-204798 (Reactome) | |||
| ANGPT1:p-5Y,S119-TEK | R-HSA-204813 (Reactome) | |||
| ANGPT1:p-5Y,S119-TEK | R-HSA-204850 (Reactome) | |||
| ANGPT1:p-5Y,S119-TEK | R-HSA-204861 (Reactome) | |||
| ANGPT1:p-5Y,S119-TEK | R-HSA-204871 (Reactome) | |||
| ANGPT1:p-5Y,S119-TEK | R-HSA-204873 (Reactome) | |||
| ANGPT1 | R-HSA-204779 (Reactome) | |||
| ANGPT2:TEK | Arrow | R-HSA-204863 (Reactome) | ||
| ANGPT2 | R-HSA-204863 (Reactome) | |||
| ANGPT4:TEK | Arrow | R-HSA-204824 (Reactome) | ||
| ANGPT4 | R-HSA-204824 (Reactome) | |||
| ATP | R-HSA-210291 (Reactome) | |||
| ATP | R-HSA-210872 (Reactome) | |||
| BSG dimer | Arrow | R-HSA-204600 (Reactome) | ||
| BSG:Integrin
alpha3beta1, alpha6beta1 | Arrow | R-HSA-204434 (Reactome) | ||
| BSG:MCTs | Arrow | R-HSA-204392 (Reactome) | ||
| BSG:MMP1(100-469) | Arrow | R-HSA-375135 (Reactome) | ||
| BSG:PPIA | Arrow | R-HSA-204485 (Reactome) | ||
| BSG:SPN | Arrow | R-HSA-204465 (Reactome) | ||
| BSG | R-HSA-204392 (Reactome) | |||
| BSG | R-HSA-204434 (Reactome) | |||
| BSG | R-HSA-204465 (Reactome) | |||
| BSG | R-HSA-204485 (Reactome) | |||
| BSG | R-HSA-204500 (Reactome) | |||
| BSG | R-HSA-204549 (Reactome) | |||
| BSG | R-HSA-204600 (Reactome) | |||
| BSG | R-HSA-375131 (Reactome) | |||
| BSG | R-HSA-375133 (Reactome) | |||
| BSG | R-HSA-375135 (Reactome) | |||
| Basigin:CD98hc complex | Arrow | R-HSA-375131 (Reactome) | ||
| Basigin:Mannose-carrying cell recognition molecules | Arrow | R-HSA-375133 (Reactome) | ||
| CAV1 | R-HSA-204549 (Reactome) | |||
| CD177 | R-HSA-202702 (Reactome) | |||
| CD244 | R-HSA-202722 (Reactome) | |||
| CD2 | R-HSA-202714 (Reactome) | |||
| CD47-binding SIRPs:CD47 | Arrow | R-HSA-202703 (Reactome) | ||
| CD47-binding SIRPs | R-HSA-202703 (Reactome) | |||
| CD47 | R-HSA-202703 (Reactome) | |||
| CD48:CD244 | Arrow | R-HSA-202722 (Reactome) | ||
| CD48 | R-HSA-202722 (Reactome) | |||
| CD58:CD2 | Arrow | R-HSA-202714 (Reactome) | ||
| CD58 | R-HSA-202714 (Reactome) | |||
| CD84 dimer | Arrow | R-HSA-202713 (Reactome) | ||
| CD84 | R-HSA-202713 (Reactome) | |||
| CD98hc complex | R-HSA-375131 (Reactome) | |||
| CEACAM heterodimer | Arrow | R-HSA-202717 (Reactome) | ||
| CEACAM heterodimer | Arrow | R-HSA-202723 (Reactome) | ||
| CXADR bound to JAML | Arrow | R-HSA-199093 (Reactome) | ||
| CXADR | R-HSA-199093 (Reactome) | |||
| Caveolin-1 bound to Basigin | Arrow | R-HSA-204549 (Reactome) | ||
| Collagen type I fibril | R-HSA-114577 (Reactome) | |||
| CyP60 complexed with Basigin | Arrow | R-HSA-204500 (Reactome) | ||
| DOK2 | R-HSA-204850 (Reactome) | |||
| E-selectin ligand | R-HSA-2870221 (Reactome) | |||
| E-selectin:ESL | Arrow | R-HSA-2870221 (Reactome) | ||
| F11R dimer | Arrow | R-HSA-202726 (Reactome) | ||
| F11R | R-HSA-202718 (Reactome) | |||
| F11R | R-HSA-202726 (Reactome) | |||
| FN1 dimer | R-HSA-202723 (Reactome) | |||
| GDP | Arrow | R-HSA-210977 (Reactome) | ||
| GPVI:FceRI gamma:FYN:LYN:Collagen type I | Arrow | R-HSA-114577 (Reactome) | ||
| GPVI:FceRI gamma:FYN:LYN | R-HSA-114577 (Reactome) | |||
| GRB14 | R-HSA-204813 (Reactome) | |||
| GRB2-1 | R-HSA-204871 (Reactome) | |||
| GRB7 | R-HSA-204773 (Reactome) | |||
| GTP | R-HSA-210977 (Reactome) | |||
| Grb2 bound to Tie2 | Arrow | R-HSA-204871 (Reactome) | ||
| Grb2 bound to Tie2 | R-HSA-210974 (Reactome) | |||
| HS | Arrow | R-HSA-204485 (Reactome) | ||
| INPP5D | R-HSA-210290 (Reactome) | |||
| Integrin
alpha3beta1, alpha6beta1 | R-HSA-204434 (Reactome) | |||
| Integrin
alpha5beta1:FN1 dimer | Arrow | R-HSA-202723 (Reactome) | ||
| Integrin alphaLbeta2:F11R | Arrow | R-HSA-202718 (Reactome) | ||
| Integrin alphaMbeta2:JAM3 | Arrow | R-HSA-202727 (Reactome) | ||
| Integrin alphaVbeta3:PECAM1 | Arrow | R-HSA-210304 (Reactome) | ||
| Integrin alphaXbeta2:JAM3 | Arrow | R-HSA-202704 (Reactome) | ||
| Integrin alpha4beta1 | R-HSA-202706 (Reactome) | |||
| Integrin alpha5beta1 | R-HSA-202723 (Reactome) | |||
| Integrin alphaLbeta2 | R-HSA-202718 (Reactome) | |||
| Integrin alphaMbeta2 | R-HSA-202727 (Reactome) | |||
| Integrin alphaVbeta3 | R-HSA-210304 (Reactome) | |||
| Integrin alphaXbeta2 | R-HSA-202704 (Reactome) | |||
| JAM2 dimer | Arrow | R-HSA-202709 (Reactome) | ||
| JAM2:JAM3 | Arrow | R-HSA-202721 (Reactome) | ||
| JAM2:JAM3 | R-HSA-202706 (Reactome) | |||
| JAM2 | R-HSA-202709 (Reactome) | |||
| JAM2 | R-HSA-202721 (Reactome) | |||
| JAM3 dimer | Arrow | R-HSA-202731 (Reactome) | ||
| JAM3 | R-HSA-202704 (Reactome) | |||
| JAM3 | R-HSA-202721 (Reactome) | |||
| JAM3 | R-HSA-202727 (Reactome) | |||
| JAM3 | R-HSA-202731 (Reactome) | |||
| LDL | R-HSA-203130 (Reactome) | |||
| Ligand to TREM-1 on
the platelet membrane | R-HSA-203156 (Reactome) | |||
| MERTK ligands | R-HSA-202710 (Reactome) | |||
| MERTK:MERKT ligands | Arrow | R-HSA-202710 (Reactome) | ||
| MERTK | R-HSA-202710 (Reactome) | |||
| MMP1(100-469) | R-HSA-375135 (Reactome) | |||
| Mannose-carrying
cell recognition molecules | R-HSA-375133 (Reactome) | |||
| Mn2+ | R-HSA-202723 (Reactome) | |||
| Monocarboxylate
Transporter Set (MCT) | R-HSA-204392 (Reactome) | |||
| Neutrophil CEACAMs
affecting integrin binding to fibronectin | R-HSA-202717 (Reactome) | |||
| OLR1 bound to oxidized LDL | Arrow | R-HSA-203130 (Reactome) | ||
| OLR1 | R-HSA-203130 (Reactome) | |||
| P-selectin bound to its ligand | Arrow | R-HSA-202724 (Reactome) | ||
| PECAM-1:PLC gamma1 complex | Arrow | R-HSA-210283 (Reactome) | ||
| PECAM-1:SHIP1 complex | Arrow | R-HSA-210290 (Reactome) | ||
| PECAM-1:SHP-1 complex | Arrow | R-HSA-210277 (Reactome) | ||
| PECAM-1:SHP-2 complex | Arrow | R-HSA-210294 (Reactome) | ||
| PECAM1 dimer | Arrow | R-HSA-210285 (Reactome) | ||
| PECAM1 dimer | R-HSA-210291 (Reactome) | |||
| PECAM1(27-?) | R-HSA-202702 (Reactome) | |||
| PECAM1(27-?) | R-HSA-210285 (Reactome) | |||
| PECAM1(27-?) | R-HSA-210304 (Reactome) | |||
| PECAM1:CD177 | Arrow | R-HSA-202702 (Reactome) | ||
| PI3K | R-HSA-204798 (Reactome) | |||
| PLCG1 | R-HSA-210283 (Reactome) | |||
| PPIA | R-HSA-204485 (Reactome) | |||
| PPIL2 | R-HSA-204500 (Reactome) | |||
| PROC(200-211) | Arrow | R-HSA-141040 (Reactome) | ||
| PROCR:Activated protein C | Arrow | R-HSA-141040 (Reactome) | ||
| PROCR:Protein C | R-HSA-141040 (Reactome) | |||
| PTPN11 | R-HSA-204873 (Reactome) | |||
| PTPN11 | R-HSA-210294 (Reactome) | |||
| PTPN6 | R-HSA-210277 (Reactome) | |||
| Phosphorylated Tie2 in Tie2/Akt dimer | Arrow | R-HSA-210872 (Reactome) | ||
| Platelet Factor 4 | Arrow | R-HSA-141040 (Reactome) | ||
| R-HSA-114577 (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. | |||
| R-HSA-141040 (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. | |||
| R-HSA-199093 (Reactome) | JAM members, such as JAML, bind coxsackie and adenovirus receptor (CXADR) on epithelial and endothelial cells. | |||
| R-HSA-202702 (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. | |||
| R-HSA-202703 (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. | |||
| R-HSA-202704 (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. | |||
| R-HSA-202706 (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 JAM2 (JAM-B) and Integrin alpha4beta1 (VLA-4) requires prior inding of JAM2 to JAM3 (JAM-C). | |||
| R-HSA-202709 (Reactome) | Apart from its well-established interaction with Integrin alpha4beta1 (VLA-4), JAM2 (JAM-B) is also known to homodimerize. | |||
| R-HSA-202710 (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. | |||
| R-HSA-202713 (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. | |||
| R-HSA-202714 (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. | |||
| R-HSA-202717 (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. | |||
| R-HSA-202718 (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. | |||
| R-HSA-202721 (Reactome) | 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. | |||
| R-HSA-202722 (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. | |||
| R-HSA-202723 (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, 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. | |||
| R-HSA-202724 (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. | |||
| R-HSA-202726 (Reactome) | 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. | |||
| R-HSA-202727 (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. | |||
| R-HSA-202731 (Reactome) | JAM-C has been detected in epithelial-cell desmosomes. JAM-C homodimers are prominently located in endothelial-cell tight junctions. | |||
| R-HSA-203130 (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. | |||
| R-HSA-203156 (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). | |||
| R-HSA-204392 (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. | |||
| R-HSA-204434 (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. | |||
| R-HSA-204465 (Reactome) | CD43, a major leukocyte cell surface sialoglycoprotein, interacts directly with Basigin. | |||
| R-HSA-204485 (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. | |||
| R-HSA-204500 (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. | |||
| R-HSA-204549 (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. | |||
| R-HSA-204600 (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. | |||
| R-HSA-204773 (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. | |||
| R-HSA-204779 (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. | |||
| R-HSA-204798 (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. | |||
| R-HSA-204813 (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. | |||
| R-HSA-204824 (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. | |||
| R-HSA-204850 (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. | |||
| R-HSA-204861 (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. | |||
| R-HSA-204863 (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. | |||
| R-HSA-204871 (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. | |||
| R-HSA-204873 (Reactome) | Shp2 interact with Tyr816 in the juxtamembrane region and Tyr1108 and Tyr1113, respectively, in the C-terminal tail region of Tie2/Tek. | |||
| R-HSA-210277 (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. | |||
| R-HSA-210283 (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. | |||
| R-HSA-210285 (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. | |||
| R-HSA-210290 (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. | |||
| R-HSA-210291 (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. | |||
| R-HSA-210294 (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. | |||
| R-HSA-210304 (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. | |||
| R-HSA-210872 (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. | |||
| R-HSA-210881 (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. | |||
| R-HSA-210974 (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. | |||
| R-HSA-210977 (Reactome) | Sos-1 bound to Grb2:Tie2 complex promotes the exchange of inactive Ras-GDP to active Ras-GTP. | |||
| R-HSA-2870221 (Reactome) | 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). | |||
| R-HSA-375131 (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. | |||
| R-HSA-375133 (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. | |||
| R-HSA-375135 (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. | |||
| SELE | R-HSA-2870221 (Reactome) | |||
| SELPLG | R-HSA-202724 (Reactome) | |||
| SHC1 | R-HSA-204861 (Reactome) | |||
| SOS-1 bound to Tie2:Grb2 | Arrow | R-HSA-210974 (Reactome) | ||
| SOS-1 bound to Tie2:Grb2 | mim-catalysis | R-HSA-210977 (Reactome) | ||
| SOS1 | R-HSA-210974 (Reactome) | |||
| SPN | R-HSA-204465 (Reactome) | |||
| Selectin | R-HSA-202724 (Reactome) | |||
| Src family tyrosine kinases (SFKs) | mim-catalysis | R-HSA-210291 (Reactome) | ||
| TEK | R-HSA-204779 (Reactome) | |||
| TEK | R-HSA-204824 (Reactome) | |||
| TEK | R-HSA-204863 (Reactome) | |||
| TREM-1 bound to its ligand | Arrow | R-HSA-203156 (Reactome) | ||
| TREM1 | R-HSA-203156 (Reactome) | |||
| Tie2 and Dok-2 complex | Arrow | R-HSA-204850 (Reactome) | ||
| Tie2 and Grb14 complex | Arrow | R-HSA-204813 (Reactome) | ||
| Tie2:Grb7 complex | Arrow | R-HSA-204773 (Reactome) | ||
| activated thrombin:thrombomodulin | mim-catalysis | R-HSA-141040 (Reactome) | ||
| integrin alpha4beta1:JAM2:JAM3 | Arrow | R-HSA-202706 (Reactome) | ||
| p-Y663,Y686-PECAM1 dimer | Arrow | R-HSA-210291 (Reactome) | ||
| p-Y663,Y686-PECAM1(27-?) | R-HSA-210277 (Reactome) | |||
| p-Y663,Y686-PECAM1(27-?) | R-HSA-210283 (Reactome) | |||
| p-Y663,Y686-PECAM1(27-?) | R-HSA-210290 (Reactome) | |||
| p-Y663,Y686-PECAM1(27-?) | R-HSA-210294 (Reactome) | |||
| p21 RAS:GDP | R-HSA-210977 (Reactome) | |||
| p21 RAS:GTP | Arrow | R-HSA-210977 (Reactome) | ||
| p85 bound to Tie2 | Arrow | R-HSA-204798 (Reactome) | ||
| pTie2 and SHP2 complex | Arrow | R-HSA-204873 (Reactome) |
