Disease relevance of VTN

• On the other hand, uPA treatment strongly increases the adhesion of anaplastic carcinoma cells specifically to VTN [1].
• The purified globulin inhibited spreading of osteosarcoma and melanoma cells on vitronectin, and of endothelial cells, platelets, and mononuclear blood cells on vitronectin or fibrinogen [2].
• Staining of lung biopsy specimens from patients with acute lung injury indicated that fibrin and vitronectin colocalize at exudative sites in which macrophages bearing these receptors accumulate [3].
• Although the role of VN as a permissive substrate for glioma migration has been well characterized, its role in conferring a survival advantage for tumor cells has not been addressed previously [4].
• VN, an ECM protein preferentially expressed at the tumor-brain interface in vivo, may confer a survival advantage to glioma cells at the advancing tumor margin and may thus, in part, underlie the high level of tumor recurrence at this interface [4].

Psychiatry related information on VTN

• Transfection of CHO cells with alpha(v)beta(3) genes significantly increased their permissiveness to all three rotavirus strains, and the increment of virus infectivity was reverted by incubation of these cells either with antibodies to beta(3) or with vitronectin [5].

High impact information on VTN

• This receptor appears to mediate cell adhesion to vitronectin as well as fibronectin since an antibody directed to its alpha subunit blocked carcinoma cell adhesion to both of these matrix proteins [6].
• The urokinase-type plasminogen activator receptor (uPAR) and integrins formed stable complexes that both inhibited native integrin adhesive function and promoted adhesion to vitronectin via a ligand binding site on uPAR [7].
• These results indicate that a rise in [Ca2+]i reduces integrin-mediated adhesion to vitronectin by a mechanism that requires calcineurin activity [8].
• Migration of human polymorphonuclear neutrophils on vitronectin is dependent on repeated transient increases in the concentration of intracellular free calcium ([Ca2+]i) [8].
• A similar reduction in motility on vitronectin occurred when cells were treated with the immunosuppressant FK506, which also inhibits calcineurin when bound to its binding protein, FKBP [8].

Chemical compound and disease context of VTN

• We have reported that metastatic human melanoma cells utilize the alpha (v)beta3 integrin to adhere to lymph node vitronectin (VN) [9].
• Likewise, unlabeled human fibronectin and heparin inhibited the binding of labeled S protein to group G streptococci, S. aureus, and E. coli, but did not influence the binding to group A and C streptococci [10].
• The binding to group G streptococci, S. aureus, and E. coli is mediated in part through a domain in the S protein containing the sequence Arg-Gly-Asp, whereas a different site is responsible for the binding to group A and C streptococci [10].
• We have analysed the occurrence of the extracellular glycoprotein vitronectin in carcinomas and normal tissue of human breast [11].
• We demonstrate here that endodermal sinus tumour cells, but not other cell types isolated from testicular teratomas, secrete the serum attachment protein, vitronectin (also known as serum-spreading factor, S-protein or epibolin), as well as fibronectin, laminin and type IV collagen, into serum-free medium [12].

Biological context of VTN

• The prolongation of uPA treatment increases cell adhesion to VTN, and, less efficiently, to other ECM components [13].
• The uPA-induced increase in MCF-7 cell migration was observed selectively on vitronectin-coated surfaces and was mediated by a beta1-integrin (probably alphaVbeta1) and alphaVbeta5 [14].
• S 36578-2 is highly selective for alphavbeta3 and alphavbeta5 integrins and induces detachment, caspase-8 activation, and apoptosis in human umbilical endothelial cells (HUVECs) plated on vitronectin [15].
• The identification of platelet VN and its binding to platelet PAI-1 raises the possibility that VN, in contrast to other adhesive proteins, may participate in localized regulatory functions of blood coagulation and fibrinolysis in platelet-matrix interactions and the protection of the matrix against proteolysis [16].
• The augmentation of phagocytosis of EA induced by vitronectin could be inhibited by the F(ab')2 fragments of anti-vitronectin IgG but not by preimmune F(ab')2 [17].

Anatomical context of VTN

• We have previously shown that uPA-R is involved in the adhesion of normal thyroid cells to VTN [13].
• Fibronectin and vitronectin regulate the organization of their respective Arg-Gly-Asp adhesion receptors in cultured human endothelial cells [18].
• Induction of Mac-1 and uPAR expression on monocytic cell lines by transforming growth factor- beta 1 and 1.25-(OH)2 vitamin D3 conferred urokinase and uPAR-dependent adhesion to vitronectin, which was further promoted by engagement of Mac-1 [3].
• These studies demonstrate that vitronectin modulates interactions between monocytes and opsonized particles [17].
• Here, we demonstrate that Zn2+ can induce the adhesion of myelomonocytic cells to the endothelium, as well as to the provisional matrix proteins vitronectin (VN) and fibrinogen (FBG), which are pivotal steps for the recruitment of leukocytes into inflamed/injured tissue [19].

Associations of VTN with chemical compounds

• In keeping with the persistence of HCs in tissues during therapy, such killing was inhibited by integrin-mediated adhesion to vitronectin or fibronectin [20].
• However, when ECs were treated with monensin only the vn receptor was organized in adhesion structures while the fn receptor was diffusely distributed [21].
• Deposition was greater when platelets were adherent to FN than to VN and was elicited by platelet agonists with the following order of potency: thrombin > LPA = ADP (adenosine diphosphate) > S1P [22].
• The adhesive glycoprotein vitronectin (VN) forms a function-stabilizing complex with plasminogen activator inhibitor-1 (PAI-1), the major fibrinolysis inhibitor in both plasma and vessel wall connective tissue [23].
• These results suggest that the cell-binding and PAI-1 binding sequences of Vn occupy distinct regions in the NH2-terminal somatomedin B domain of the molecule [24].
• Alphavbeta3 integrin was identified as the major cellular receptor for vitronectin-mediated adherence and uptake of pneumococci [25].

Physical interactions of VTN

• Both receptors promote degradation of fibrin(ogen) and also confer adhesive properties on cells because Mac-1 and uPAR bind fibrin and vitronectin, respectively [3].
• Purification and characterization of a plasminogen activator inhibitor 1 binding protein from human plasma. Identification as a multimeric form of S protein (vitronectin) [26].
• Here we report that the peptide GPIIb alpha 300-312 (G13) inhibits platelet aggregation and binds Fg and Vn [27].
• Only bacterial strains with significant S protein binding but weak fibronectin binding were included in these studies [28].
• These studies were conducted to determine if vitronectin bound IGFBP-5 with high affinity and if this altered the ability of either protein to modify cellular responsiveness to IGF-I [29].

Enzymatic interactions of VTN

• We found that Vn is indeed selectively phosphorylated by CK2 and that this phosphorylation is uPA-regulated in VSMC [30].
• The interference of S protein with glycosaminoglycan-catalyzed inhibition of thrombin by heparin cofactor II was investigated in these studies [31].
• The vitronectin receptor was more highly phosphorylated in cord-forming endothelial cells on basement membrane than in monolayer cells on vitronectin [32].
• Investigation of paxillin phosphorylation by two-dimensional phosphoamino acid analysis indicates that paxillin is 99% phosphorylated on serine residue(s) in response to vitronectin adhesion, and only 1% phosphorylated on tyrosine [33].

Co-localisations of VTN

• CK2 localization at the cell surface was highly dynamic; Vn induced formation of clusters where CK2 colocalized with uPAR and alpha(v)beta(3) integrins [30].
• CLSM image analysis confirmed that the b-Vn was internalized and that it colocalized with PAI-1 in storage granules [34].
• Clusterin protein colocalized with the membrane attack complex of complement and vitronectin in the center of the largest Hassal's bodies, but was not detectable by immunocytochemistry in or at the surface of epithelial cells [35].

Regulatory relationships of VTN

• Moreover, downregulation of PAI-1 significantly enhanced the ability of endothelial cells to adhere to vitronectin, and this effect could be reversed upon addition of recombinant PAI-1 [36].
• However, TIL did express high levels of urokinase-type plasminogen activator receptor (uPAR) and inhibitory antibodies and amiloride both significantly inhibited TIL adhesion to vitronectin and reduced transendothelial migration of lymphocytes across liver endothelium in vitro [37].
• Plasminogen activator inhibitor type 1 promotes fibrosarcoma cell migration by modifying cellular attachment to vitronectin via alpha(v)beta(5) integrin [38].
• In tumor spheroid outgrowth assays, cell migration of MT-MMP-1 transfectants relative to control was enhanced on collagen and decreased on vitronectin and fibronectin [39].
• BMP-2 increases the levels of these integrins on osteoblast surface and enhances HOB adhesion to osteopontin and vitronectin [40].

Other interactions of VTN

• The shape of receptor clusters was slightly different and a colocalization of the two receptors was found when ECs were cultured on a mixed matrix of fn plus vn [18].
• Together, these results suggest a VN-independent, uPA-uPAR-dependent mechanism by which PAI-1 induces cell detachment [41].
• Through these interactions, HKa or its recombinant His-Gly-Lys-rich domain 5 completely inhibited the uPAR-dependent adhesion of myelomonocytic U937 cells and uPAR-transfected BAF-3 cells to VN and thereby promoted cell detachment [42].
• Thus, VN-mediated uPA binding to cells was regulated by the ratio of soluble to surface-associated uPAR [43].
• No evidence for adhesion to vitronectin through CD29 and beta 5 integrins was obtained [44].

Analytical, diagnostic and therapeutic context of VTN

• A specific enzyme-linked immunosorbent assay (ELISA) for VN has been developed and was used to detect and to quantitate VN in detergent extracts of washed platelets with 8.1 +/- 4.6 micrograms/10(9) platelets (n = 10), representing about 0.8% of the plasma VN pool [16].
• Platelet and plasma VN were similar by immunochemical criteria using Western-blot analysis, although platelet VN was mainly found as partially proteolyzed polypeptide [16].
• By immunogold electron microscopy, both VN and HK/HKa were found to be colocalized in sections from human atherosclerotic coronary artery, indicating that the described interactions are likely to take place in vivo [42].
• The gel filtration behavior, mobility on sodium dodecyl sulfate-gel electrophoresis, and concentration in plasma suggest that PAI-1-BP is a multimer (presumably a dimer) of S protein accounting for approximately 35% of the S protein in plasma [26].
• Specific immunoprecipitation of newly synthesized urokinase indicated that cells adherent to fibronectin synthesized 2-3-fold more urokinase than cells adherent to vitronectin [45].

References