A Region in Urokinase Plasminogen Receptor Domain III Controlling a Functional Association with α5β1 Integrin and Tumor Growth

Chaurasia, Pratima; Aguirre‐Ghiso, Julio A.; Liang, Olin D.; Gårdsvoll, Henrik; Ploug, Michael; Ossowski, Liliana

doi:10.1074/jbc.m512311200

Cited by 113 publications

(118 citation statements)

References 43 publications

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“…Prior work in cells that express high levels of u-PAR, either de novo in neoplastic cells or experimentally induced, demonstrates that putative u-PAR-interacting partners, physiological consequences on cell physiology, and activation of intracellular signaling pathways vary depending on the levels of u-PAR and with the cell type (13,32,46,51,65). These studies also show that u-PAR will bind the somatomedin B (SMB) domain of vitronectin directly (K d Ͻ 20 nM), an interaction that is enhanced upon u-PAR ligation with u-PA (49,69).…”

Section: Discussionmentioning

confidence: 99%

Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins

Zhu

Gladson

White

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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MA. Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins. Am J Physiol Lung Cell Mol Physiol 297: L97-L108, 2009. First published May 1, 2009 doi:10.1152/ajplung.90283.2008.-Fibroblasts from patients with pulmonary fibrosis express higher levels of the receptor for urokinase, and the extent of fibrosis in some animal models exhibits a dependence on the urokinase receptor. Recent observations have identified the urokinase receptor as a trans-interacting receptor with consequences on signaling and cell responses that vary depending on its interacting partner, the relative levels of expression, and the state of cellular transformation. We undertook this study to define the urokinase-type plasminogen activator cellular receptor (u-PAR)-integrin interactions and to determine the functional consequences of such interactions on normal human lung fibroblast attachment and migration. u-PAR colocalizes in lammelipodia/filopodia with relevant integrins that mediate fibroblast attachment and spreading on the provisional matrix proteins vitronectin, fibronectin, and collagens. Inhibitory antibody studies have revealed that human lung fibroblasts utilize ␣ v␤5 to attach to vitronectin, predominantly ␣5␤1 (and ␣v␤3) to attach to fibronectin, and ␣ 1␤1, ␣2␤1, and ␣3␤1 to attach to collagen. Blocking studies with ␣-integrin subunit decoy peptides and u-PAR neutralizing antibodies indicate that u-PAR modulates the integrinmediated attachment to purified provisional matrix proteins, to antiintegrin antibodies, or to fibroproliferative lesions from fibrotic lungs. Furthermore, these decoy peptides blunt fibroblast spreading and migration. We show that u-PAR can interact with multiple ␣-integrins but with a preference for ␣ 3. Taken together, these data demonstrate that u-PAR may interact with multiple integrins in normal human lung fibroblasts thereby promoting attachment, spreading, and migration. Modulation of fibroblast invasion would be expected to lead to amelioration of fibroproliferative diseases of the lung. pulmonary; fibrosis; plasmin STUDIES IN VITRO AND IN TRANSGENIC animals have demonstrated that the fibrinolytic system has protean effects on numerous disease processes including acute and chronic inflammatory disorders, cancer invasion and metastasis, angiogenesis, and fibroproliferative disorders of the vasculature, lung, kidney, and eye (3,4,11,16,22,23,27,29,37,55). These disorders have the common feature of a complex, yet coordinated movement of cells and the biochemical and structural remodeling of the extracellular matrix. The molecular interactions and cell biological processes that mediate the effects of the fibrinolytic system on cell-matrix interactions are active areas of investigation.Protease-protease inhibitor mechanisms of the urokinase/ plasmin system that relate to intravascular or alveolar fibrin turnover are deranged in pulmonary fibrosis but are clearly only a part of the relevant biology (38). The recep...

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Section: Discussionmentioning

confidence: 99%

Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins

Zhu

Gladson

White

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The D1 domain of uPAR is required for the association of uPAR with integrin, and signaling (Liu et al, 2002;Montuori et al, 2002). At least in one case, the uPAR-integrin interaction site has been mapped within the ␣5 propeller (residues 242-246) of ␣5␤1 integrin (Wei et al, 2005;Simon et al, 2000) and within domain III of uPAR (Chaurasia et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Activation of urokinase receptor by a novel interaction between the connecting peptide region of urokinase and αvβ5 integrin

Franco

Vocca

Carriero

et al. 2006

Journal of Cell Science

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The serine protease urokinase (uPA) binds to the urokinase receptor (uPAR) through its growth-factor domain (GFD, residues 1-49), affecting cell migration, adhesion and growth. Here, we show that uPA can promote cytoskeletal rearrangements and directional cell migration in a GFD-independent manner, through a new and specific interaction between an internal uPA domain coined `connecting peptide' (residues 132-158) and cell-surface integrin αvβ5. Remarkably, a peptide corresponding to this region (CPp, residues 135-158) retains the ability to bind to αvβ5, eliciting cytoskeletal rearrangements and directing cell migration at a concentration as low as 1-10 pM. These effects are lost in cells not expressing uPAR, indicating that the uPAR is required for CPp-dependent signaling. Furthermore, the CPp-αvβ5-integrin interaction enhances F-actin-enriched protrusions and cell migration induced by the well-established interaction between the uPAR-binding peptide (GFDp, residues 12-32) of uPA and uPAR. These results provide new insight into the function of uPA, which - through individual domains - can engage two different surface receptors (uPAR and αvβ5 integrin), thus initiating and potentiating intracellular signaling and migration.

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“…9) and in uPAR domain DIII (residues 240-248; ref. 10). Moreover, uPAR cross-talk with EGF receptor (EGFR) is extensive and may regulate the shift from tumor cell dormancy to proliferation (11,12).…”

Section: Introductionmentioning

confidence: 99%

Discovery of New Small Molecules Targeting the Vitronectin-Binding Site of the Urokinase Receptor That Block Cancer Cell Invasion

Rea

Lavecchia

Giovanni

et al. 2013

Molecular Cancer Therapeutics

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Besides focusing urokinase (uPA) proteolytic activity on the cell membrane, the uPA receptor (uPAR) is able to bind vitronectin, via a direct binding site. Furthermore, uPAR interacts with other cell surface receptors, such as integrins, receptor tyrosine kinases, and chemotaxis receptors, triggering cell-signaling pathways that promote tumor progression. The ability of uPAR to coordinate binding and degradation of extracellular matrix (ECM) and cell signaling makes it an attractive therapeutic target in cancer. We used structure-based virtual screening (SB-VS) to search for small molecules targeting the uPAR-binding site for vitronectin. Forty-one compounds were identified and tested on uPAR-negative HEK-293 epithelial cells transfected with uPAR (uPAR-293 cells), using the parental cell line transfected with the empty vector (V-293 cells) as a control. Compounds 6 and 37 selectively inhibited uPAR-293 cell adhesion to vitronectin and the resulting changes in cell morphology and signal transduction, without exerting any effect on V-293 cells. Compounds 6 and 37 inhibited uPAR-293 cell binding to vitronectin with IC 50 values of 3.6 and 1.2 mmol/L, respectively. Compounds 6 and 37 targeted S88 and R91, key residues for uPAR binding to vitronectin but also for uPAR interaction with the fMLF family of chemotaxis receptors (fMLF-Rs). As a consequence, compounds 6 and 37 impaired uPAR-293 cell migration toward fetal calf serum (FCS), uPA, and fMLF, likely by inhibiting the interaction between uPAR and FPR1, the high affinity fMLF-R. Both compounds blocked in vitro ECM invasion of several cancer cell types, thus representing new promising leads for pharmaceuticals in cancer.

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A Region in Urokinase Plasminogen Receptor Domain III Controlling a Functional Association with α5β1 Integrin and Tumor Growth

Cited by 113 publications

References 43 publications

Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins

Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins

Activation of urokinase receptor by a novel interaction between the connecting peptide region of urokinase and αvβ5 integrin

Discovery of New Small Molecules Targeting the Vitronectin-Binding Site of the Urokinase Receptor That Block Cancer Cell Invasion

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