Urokinase-type Plasminogen Activator Receptor (CD87) Is a Ligand for Integrins and Mediates Cell-Cell Interaction

Tarui, Takehiko; Mazar, Andrew P.; Cines, Douglas B.; Takada, Yoshikazu

doi:10.1074/jbc.m008220200

Cited by 165 publications

(134 citation statements)

References 56 publications

(39 reference statements)

Supporting

Mentioning

128

Contrasting

Order By: Relevance

“…This is not surprising since interactions of uPAR with integrins have been observed in several cell types (Bohuslav et al, 1995;Wei et al, 1996;Yebra et al, 1996;Xue et al, 1997;May et al, 1998;Chavakis et al, 1998;Carriero et al, 1999;Simon et al, 2000). Direct interactions between uPAR and avb3 has also been reported (Tarui et al, 2000). Thus VN and pro-uPA chemotactic activity appear to be linked mechanistically already at the level of their receptors.…”

Section: Vn and Pro-upa Have Additive Effects On Rsmc Migrationmentioning

confidence: 87%

“…Direct interactions of uPAR with integrins has been shown by several techniques, including¯uorescence resonance energy transfer and co-immuno-precipitation (Bohuslav et al, 1995;Wei et al, 1996;Yebra et al, 1996;Xue et al, 1997;Carriero et al, 1999Simon et al, 2000. Speci®cally, association of uPAR with a v b 3 -expressing cells has also been reported (Tarui et al, 2000). Indeed, in leukocytes uPA regulates co-localization of b2-integrins and uPAR (Xue et al, 1997), in RSMC pro-uPA induces the co-localization of uPAR and a v b 3 to the ru es of the plasma membrane (Degryse et al, 1999), while in ®broblasts adhesion on VN induces colocalization of uPAR and a v b 3 (Ciambrone and McKeown-Longo, 1992).…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Urokinase/urokinase receptor and vitronectin/αvβ3 integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways

et al. 2001

View full text Add to dashboard Cite

Vitronectin (VN) and pro-urokinase (pro-uPA) stimulated migration of rat smooth muscle cells in a dosedependent and additive way, and induced motile-type changes in cell morphology together with a complete reorganization of the actin ®laments and of the microtubules. All these e ects were inhibited by pertussis toxin, or by antibodies directed against the urokinase receptor (uPAR) or against the VN receptor a v b 3 suggesting that an association between the two receptors is required to mediate both signals. Investigation of the signaling pathways showed that increasing the intracellular cAMP resulted in a selective inhibition of VNinduced cell migration. On the other hand, PD 98059, an inhibitor of MEK, di erentially inhibited the pro-uPAbut not the VN-induced cell migration. Phosphorylation and nuclear translocation of Erk by pro-uPA was directly observed. We conclude that the signaling pathways of pro-uPA and VN must be at least in part di erent. Oncogene (2001Oncogene ( ) 20, 2032Oncogene ( ± 2043

show abstract

Section: Vn and Pro-upa Have Additive Effects On Rsmc Migrationmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 98%

Urokinase/urokinase receptor and vitronectin/αvβ3 integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways

et al. 2001

View full text Add to dashboard Cite

show abstract

“…On a molecular level, this suggests that the association of integrins with the uPA⅐uPAR complex (27,28,32,35) may serve to correctly position this complex in close proximity to the cryptic vitronectin RGD adhesion site that becomes accessible upon binding of uPA to PAI-1 and subsequent dissociation of the PAI-1⅐uPA complex from vitronectin (36). Thus, uPA/uPAR may serve to escort the integrin to the appropriate high affinity binding site within the matrix.…”

Section: Tumor Sections Treated With Pbs (A D G) Partially Inactivmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 Regulates Tumor Growth and Angiogenesis

McMahon¹,

Petitclerc²,

Stefansson³

et al. 2001

Journal of Biological Chemistry

247

190

View full text Add to dashboard Cite

Elevated expression of plasminogen activator inhibitor-1 (PAI-1) in tumors is associated with a poor prognosis in many cancers. Reduced tumor growth and angiogenesis have also been reported in mice deficient in PAI-1. These results suggest that PAI-1 may be required for efficient angiogenesis and tumor growth. In the present study, we demonstrate that PAI-1 can both enhance and inhibit the growth of M21 human melanoma tumors in nude mice and that this appears to be due to PAI-1 regulation of angiogenesis. Quantitative analysis of angiogenesis in a Matrigel implant assay indicated that in PAI-1 null mice angiogenesis was reduced ϳ60% compared with wild-type mice, while in mice overexpressing PAI-1, angiogenesis was increased nearly 3-fold. Furthermore, addition of PAI-1 to implants in wild-type mice enhanced angiogenesis up to 3-fold at low concentrations but inhibited angiogenesis nearly completely at high concentrations. Together, these data demonstrate that PAI-1 is a potent regulator of angiogenesis and hence of tumor growth and suggest that understanding the mechanism of this activity may lead to the development of important new therapeutic agents for controlling pathologic angiogenesis.

show abstract

“…There is a close interplay between uPAR, integrins, vitronectin, and PAI-1 in regulating cell invasiveness. Multiple lines of evidence exist for association of uPAR with integrins to coordinate the effects of the two classes of receptors in mediating signaling and promoting cellular rearrangement and/or migration (57)(58)(59)(60)(61)(62)(63)(64)(65). This new information defining the relative location of binding sites for PAI-1 and the two receptors within the SMB domain will be invaluable for considering mechanisms by which these receptors and the ECM communicate in a reciprocal manner, ultimately with the goal of developing new antitumor and anti-thrombotic agents.…”

Section: Figmentioning

confidence: 99%

The Solution Structure of the N-terminal Domain of Human Vitronectin

Mayasundari¹,

Whittemore²,

Serpersu

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The three-dimensional structure of an N-terminal fragment comprising the first 51 amino acids from human plasma vitronectin, the somatomedin B (SMB) domain, has been determined by two-dimensional NMR approaches. An average structure was calculated, representing the overall fold from a set of 20 minimized structures. The core residues (18 -41) overlay with a root mean square deviation of 2.29 ؎ 0.62 Å. The N-and Cterminal segments exhibit higher root mean square deviations, reflecting more flexibility in solution and/or fewer long-range NOEs for these regions. Residues 26 -30 form a unique single-turn ␣-helix, the locus where plasminogen activator inhibitor type-1 (PAI-1) is bound. This structure of this helix is highly homologous with that of a recombinant SMB domain solved in a co-crystal with PAI-1 (Zhou, A., Huntington, J. A., Pannu, N. S., Carrell, R. W., and Read, R. J. (2003) Nat. Struct. Biol. 10, 541-544), although the remainder of the structure differs. Significantly, the pattern of disulfide cross-links observed in this material isolated from human plasma is altogether different from the disulfides proposed for recombinant forms. The NMR structure reveals the relative orientation of binding sites for cell surface receptors, including an integrin-binding site at residues 45-47, which was disordered and did not diffract in the co-crystal, and a site for the urokinase receptor, which overlaps with the PAI-1-binding site.Human vitronectin is a glycoprotein found in the circulation, where it contributes to hemostasis by regulating blood coagulation and fibrinolysis (1, 2). Vitronectin is also found in the ECM, 1 where it plays important roles in cell adhesion, pericellular proteolysis, tissue invasion, angiogenesis, and metastasis (3-7). The variety of functions of vitronectin in the two microenvironments is a manifestation of its ability to interact with numerous humoral and cellular proteins. An important binding partner for vitronectin is the serine protease inhibitor PAI-1, which also is found both in circulation and the ECM. Furthermore, it has different activities depending upon this localization; the anti-protease activity of PAI-1 that regulates thrombolysis in the circulation is targeted instead toward pericellular proteolysis when localized to the ECM or cell/matrix boundary. Vitronectin binds to PAI-1 with high affinity and stabilizes the inhibitor in its active conformation (8, 9). Vitronectin can also associate with PAI-1 and assemble to form higher order complexes (10) that exhibit altered adhesive functions (11). Key to the adhesive functions of vitronectin are its interactions with cell-surface receptors including integrins and uPAR.A widely accepted model suggests that vitronectin is organized into functional domains that provide the broad repertoire necessary for binding to target ligands (12)(13)(14). We recently used computational methods to predict the structure of the three domains comprising vitronectin (15). A threading algorithm gave high confidence predictions for the central domai...

show abstract

Urokinase-type Plasminogen Activator Receptor (CD87) Is a Ligand for Integrins and Mediates Cell-Cell Interaction

Cited by 165 publications

References 56 publications

Urokinase/urokinase receptor and vitronectin/αvβ3 integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways

Urokinase/urokinase receptor and vitronectin/αvβ3 integrin induce chemotaxis and cytoskeleton reorganization through different signaling pathways

Plasminogen Activator Inhibitor-1 Regulates Tumor Growth and Angiogenesis

The Solution Structure of the N-terminal Domain of Human Vitronectin

Contact Info

Product

Resources

About