Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization

Selleri, Carmine; Montuori, Nunzia; Ricci, Patrizia; Visconte, Valeria; Carriero, Maria Vincenza; Sidénius, Nicolai; Serio, Bianca; Blasi, Francesco; Rotoli, Bruno; Rossi, Guido; Ragno, Pia

doi:10.1182/blood-2004-06-2424

Cited by 93 publications

(120 citation statements)

References 58 publications

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“…These effects are mediated by interactions with the extracellular domains of transmembrane proteins including integrins, low density lipoprotein receptor-related protein, epidermal growth factor (EGF) receptor, platelet derived growth factor (PDGF) receptor and the G-proteincoupled receptors FPRL1 (FMLP-Receptor-Like Protein 1) and FPR (FMLP-Receptor) (Blasi and Carmeliet, 2002;Kiyan et al, 2005;Selleri et al, 2005). Several evidences underline a direct participation of uPAR in controlling cell proliferation (Mazzieri and Blasi, 2005).…”

Section: Introductionmentioning

confidence: 99%

A direct link between expression of urokinase plasminogen activator receptor, growth rate and oncogenic transformation in mouse embryonic fibroblasts

et al. 2006

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In addition to its role in invasion and metastasis of several tumors, the multifunctional urokinase receptor uPAR (urokinase plasminogen activator receptor) is directly involved in the growth of several cancer cells in vitro and in vivo. We have compared growth rate and oncogenic transformation in wild-type (wt) or uPAR À/À mouse embryonic fibroblasts (MEFs). Surprisingly, uPAR À/À MEFs grew faster than wt MEFs. This agreed with elevated levels of cell cycle mediators like extracellular signal-regulated protein kinase, p38, AP1 and Cyclin D1. Infection with a uPAR retrovirus reverted the effect, decreasing the growth rate.When MEFs were transformed with H-Ras V12 and E1A oncogenes, the efficiency of transformation in uPAR À/À MEFs was higher than in wt. UPAR À/À MEFs grew faster at low serum, produced more colonies in agar and produced tumors in vivo in nude mice with a lower latency period. The properties of the heterozygous uPAR þ /À MEFs were always intermediate. We conclude therefore that in MEFs uPAR concentration controls cell proliferation and the transforming activity of some oncogenes.

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Section: Introductionmentioning

confidence: 99%

A direct link between expression of urokinase plasminogen activator receptor, growth rate and oncogenic transformation in mouse embryonic fibroblasts

et al. 2006

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“…87 On G-CSF treatment, uPAR is cleaved from the cell surface by plasmin 87 and released into the extracellular space, wherein it is subsequently proteolytically cleaved into smaller fragments. 88 Selleri et al 89 suggest that…”

Section: Regulation Of Hspc Mobilization By Uparmentioning

confidence: 99%

Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization

2010

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“…uPAR is a glycosylated glycosyl-phosphatidyl-inositol-anchored protein (4) formed by 3 domains (DI, DII, and DIII) connected by short linker regions (5). Besides being responsible for focalizing uPA-mediated plasminogen activation on cell surface (6), uPAR also promotes intracellular signaling, thus regulating physiologic processes such as wound healing, immune responses, and stem cell mobilization, as well as pathologic conditions such as inflammation and tumor progression (7)(8)(9)(10). The role of uPAR in angiogenesis is well documented.…”

Section: Introductionmentioning

confidence: 99%

“…We found that soluble forms of uPAR, containing the 88 Ser-Arg-Ser-Arg-Tyr 92 sequence (uPAR [88][89][90][91][92] ), as well as the synthetic peptide Ser-Arg-Ser-Arg-Tyr (SRSRY), stimulates in vitro and in vivo angiogenesis in a protease-independent manner (13). The uPAR 88-92 sequence interacts with the formyl peptide receptors (FPR) type 1 and 2, henceforth inducing cell migration in an integrin-dependent manner (9,14,15). Upon binding to FPR, the synthetic peptide SRSRY causes FPR internalization and triggers vitronectin receptor activation with an inside-outside type of mechanism (16).…”

Section: Introductionmentioning

confidence: 99%

UPARANT: A Urokinase Receptor–Derived Peptide Inhibitor of VEGF-Driven Angiogenesis with Enhanced Stability and In Vitro and In Vivo Potency

Carriero

Bifulco²,

Minopoli

et al. 2014

Molecular Cancer Therapeutics

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This work is based on previous evidence showing that chemotactic sequence of the urokinase receptor (uPAR [88][89][90][91][92] ) drives angiogenesis in vitro and in vivo in a protease-independent manner, and that the peptide AcArg-Glu-Arg-Phe-NH 2 (RERF) prevents both uPAR 88-92 -and VEGF-induced angiogenesis. New N-acetylated and C-amidated peptide analogues containing a-methyl a-amino acids were designed and synthesized to optimize the biochemical properties for therapeutic applications. Among these, Ac-L-Arg-Aib-L-Arg-D-Ca(Me) Phe-NH 2 , named UPARANT, adopts in solution a turned conformation similar to that found for RERF, is stable to sterilization in 3 mg/mL sealed vials in autoclave for 20 minutes at 120 C, is stable in blood, and displays a long-time resistance to enzymatic proteolysis. UPARANT competes with N-formyl-Met-Leu-Phe (fMLF) for binding to the formyl-peptide receptor, inhibits VEGF-directed endothelial cell migration, and prevents cytoskeletal organization and avb3 activation in endothelial cells exposed to VEGF. In vitro, UPARANT inhibits VEGF-dependent tube formation of endothelial cells at a 100Â lower concentration than RERF. In vivo, UPARANT reduces to the basal level VEGF-dependent capillary sprouts originating from the host vessels that invaded Matrigel sponges implanted in mice, and completely prevents neovascularization induced by subcorneal implantation of pellets containing VEGF in rabbits. Both excellent stability and potency position UPARANT as a promising new therapeutic agent for the control of diseases fueled by excessive angiogenesis, such as cancer and inflammation.

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Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization

Cited by 93 publications

References 58 publications

A direct link between expression of urokinase plasminogen activator receptor, growth rate and oncogenic transformation in mouse embryonic fibroblasts

A direct link between expression of urokinase plasminogen activator receptor, growth rate and oncogenic transformation in mouse embryonic fibroblasts

Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization

UPARANT: A Urokinase Receptor–Derived Peptide Inhibitor of VEGF-Driven Angiogenesis with Enhanced Stability and In Vitro and In Vivo Potency

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