Direct Binding of Occupied Urokinase Receptor (uPAR) to LDL Receptor-related Protein Is Required for Endocytosis of uPAR and Regulation of Cell Surface Urokinase Activity

Czekay, Ralf-Peter; Kuemmel, Thomas A.; Orlando, Robert A.; Farquhar, Marilyn G.

doi:10.1091/mbc.12.5.1467

Cited by 167 publications

(168 citation statements)

References 54 publications

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“…Inactive uPA-PAI-1 complexes bound to uPAR are rapidly internalized and degraded in lysosomes, whereas unoccupied uPAR returns to the cell surface. 40 SCH-66336 does not appear to directly interfere with these processes. For instance, while the total amount of secreted uPA from PC-3 cells decreases in the presence of SCH-66336, uPAR levels remain stable, likely allowing pro-uPA processing into active uPA.…”

Section: Discussionmentioning

confidence: 85%

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

Desrosiers

Cusson

Turcotte

et al. 2005

Intl Journal of Cancer

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The ras oncogenes are among those most frequently found in human cancers. Blocking Ras farnesylation is a promising strategy for arresting cancer growth. Ras activates several signaling pathways with key roles in cellular proliferation, invasion, metastasis and angiogenesis. Furthermore, proteolytic activities of matrix proteinases such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) are regulated by Ras isoforms. Thus, we investigated the effects of SCH-66336, a farnesyltransferase inhibitor, on secretion of components of the plasminogen activation system as well as on the gelatinases MMP-2 and MMP-9, which play pivotal roles in matrix remodeling. SCH-66336 up to 5 M did not significantly alter the viability of prostate (PC-3) and renal (Caki-1) cancer cells incubated in serum-depleted medium. SCH-66336 partly inhibited the processing of H-Ras, while levels of mature N-Ras and K-Ras remained unaffected. Under these noncytotoxic conditions, uPA and tPA levels were lowered in culture medium but raised in cell lysates, suggesting inhibition of trafficking pathways. In contrast, SCH-66336 had no effect on uPAR expression or on secreted PAI-1 levels. As expected, the reduction of uPA and tPA activities by SCH-66336 inhibited the conversion of plasminogen to plasmin by about 25% in PC-3 cells. SCH-66336 also inhibited the levels of secreted pro-MMP-2 and pro-MMP-9 as well as the release of their inhibitors TIMP-1 and TIMP-2. SCH-66336 decreased both the adhesion and even more so the migration of PC-3 cells on gelatin. Thus, SCH-66336 inhibited farnesylation in both cancer cell types, and H-Ras functions should be reduced by the drug. In addition, the lower levels of secreted proteinases in the presence of SCH-66336 suggest that reduced matrix remodeling and cell migration should occur in treated tumors.

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Section: Discussionmentioning

confidence: 85%

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

Desrosiers

Cusson

Turcotte

et al. 2005

Intl Journal of Cancer

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“…Under physiological conditions, uPA bound to uPAR catalyzes the conversion of plasminogen to plasmin, which in turn degrades the ECM and facilitates cell migration [Chazaud et al, 2000]. The binding of PAI-1 to uPA inactivates uPA, triggers the recruitment of uPAR by LRP and the formation of a quaternary complex [uPAR Á uPA Á PAI-1 Á LRP] for endocytosis [Chazaud et al, 2000;Czekay et al, 2001]. Subsequently, intracellular degradation of the complex occurs with recycling of uPAR and LRP back to the cell surface [Nykjaer et al, 1997].…”

Section: Discussionmentioning

confidence: 99%

Anthocyanidins inhibit migration of glioblastoma cells: Structure‐activity relationship and involvement of the plasminolytic system

Lamy

Lafleur

Bédard

et al. 2006

J of Cellular Biochemistry

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Complete resection of malignant glioblastomas is usually impossible because of diffuse and widespread invasion of tumor cells, and complementary approaches need to be developed in order to improve the efficacy of current treatments. Consumption of fruits and berries has been associated with decreased risk of developing cancer and there is great interest in the use of molecules from dietary origin to improve anticancer therapies. In this work, we report that the aglycons of the most abundant anthocyanins in fruits, cyanidin (Cy), delphinidin (Dp), and petunidin (Pt), act as potent inhibitors of glioblastoma cell migration. Dp clearly exhibited the highest inhibitory potency, this effect being related to the ortho-dihydroxyphenyl structure on the B-ring and the presence of a free hydroxyl group at position 3. Dp decreases the expression of both urokinase-type plasminogen activator receptor (uPAR) and the low-density lipoprotein receptor-related protein (LRP), acting at the transcriptional levels. In addition, Dp upregulated urokinase-type plasminogen activator (uPA) and downregulated the plasminogen activator inhibitor-1 (PAI-1) but decreased, in a concentration-dependent manner, the uPA-dependent conversion of plasminogen to plasmin, indicating that the upregulation of uPA observed with these compounds was not associated with induction of the plasminolytic activity. Overall, these results demonstrate that Dp, Pt, and Cy affect plasminogen activation, thus leading to the inhibition of glioblastoma cell migration and therefore they may be helpful for the development of new strategies for cancer prevention and therapy.

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“…LRP-mediated internalization of uPA⅐PAI-1⅐uPAR complexes results in the lysosomal degradation of uPA and PAI-1 and recycling of uPAR to the cell surface (4 -7). This process allows for the regeneration of unoccupied uPAR, immobilization of fresh uPA in the form of its zymogen, pro-uPA, and the eventual re-expression of active uPA at the cell surface (8,10). Failure to remove uPA⅐PAI-1complexes from the cell surface may diminish the cellular capacity for plasminogen activation and may impair cell migration/invasion mediated by uPAR (8 -10, 26).…”

Section: Discussionmentioning

confidence: 99%

“…uPAR⅐LRP complexes are then endocytosed via clathrin-coated vesicles and traffic together to early endosomes (10). To examine whether uPAR and mLRP1B4 form a molecular complex after binding of uPA⅐PAI-1, we analyzed the potential interaction between uPAR and mLRP1B4 on the plasma membrane by carrying out cross-linking experiments in the presence of recombinant soluble (lacking the glycosylphosphatidylinositolanchor) uPAR (amino acids 1-281).…”

Section: Internalization Rate Of Upa⅐pai-1 Complexes By Mlrp1b4mentioning

confidence: 99%

Low Density Lipoprotein (LDL) Receptor-related Protein 1B Impairs Urokinase Receptor Regeneration on the Cell Surface and Inhibits Cell Migration

Knisely²,

Lü³

et al. 2002

Journal of Biological Chemistry

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The low density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a newly identified member of the LDL receptor family and is closely related to LRP. It was discovered as a putative tumor suppressor and is frequently inactivated in lung cancer cells. In the present study, we used an LRP1B minireceptor (mLRP1B4), which mimics the function and trafficking of LRP1B, to explore the roles of LRP1B on the plasminogen activation system. We found that mLRP1B4 and urokinase plasminogen activator receptor (uPAR) form immunoprecipitable complexes on the cell surface in the presence of complexes of uPA and its inhibitor, plasminogen activator inhibitor type-1 (PAI-1). However, compared with cells expressing the analogous LRP minireceptor (mLRP4), cells expressing mLRP1B4 display a substantially slower rate of uPA⅐PAI-1 complex internalization. Expression of mLRP1B4, or an mLRP4 mutant deficient in endocytosis, leads to an accumulation of uPAR at the cell surface and increased cell-associated uPA and PAI-1 when compared with cells expressing mLRP4. In addition, we found that expression of mLRP1B or the mLRP4 endocytosis mutant impairs the regeneration of unoccupied uPAR on the cell surface and that this correlates with a diminished rate of cell migration. Taken together, these results demonstrate that LRP1B can function as a negative regulator of uPAR regeneration and cell migration.The plasminogen activation system consists of a cascade of enzymes and plays a central role in many physiological processes requiring the degradation of basement membrane and components of the extracellular matrix. When the regulation of this system is disrupted, as occurs in the pathogenesis of cancer, malignant cells are able to invade surrounding tissue and metastasize to distant body regions (1-3). Urokinase plasminogen activator (uPA) 1 catalyzes the formation of plasmin from its inactive precursor, plasminogen. The activity of uPA is regulated by two proteins, the glycosylphosphatidylinositollinked uPA receptor (uPAR) and plasminogen activator inhibitor type 1 (PAI-1). The binding of uPA to uPAR at the cell surface greatly increases its catalytic rate. In contrast, uPA is inactivated by binding to PAI-1. When active uPA is bound to uPAR, it is not internalized but remains at the cell surface. However, when receptor-bound uPA is complexed to its inhibitor, PAI-1, the complex is rapidly internalized and degraded. The mechanism by which this occurs was unknown until it was determined that low density lipoprotein receptor-related protein (LRP) is responsible for this process (4). Following the internalization, uPAR and LRP recycle back to the cell surface, while uPA and PAI-1 are degraded in lysosomes (4 -7). The regeneration of unoccupied uPAR at the cell surface is thus critical for the maintenance of plasminogen activation and for regulation of cellular migration and invasion (8 -10).LRP1B is a recently discovered member of the LDLR family (11, 12). The LDLR family previously contained two large members, LRP (LRP1), a dimer of 515-and...

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Direct Binding of Occupied Urokinase Receptor (uPAR) to LDL Receptor-related Protein Is Required for Endocytosis of uPAR and Regulation of Cell Surface Urokinase Activity

Cited by 167 publications

References 54 publications

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

Anthocyanidins inhibit migration of glioblastoma cells: Structure‐activity relationship and involvement of the plasminolytic system

Low Density Lipoprotein (LDL) Receptor-related Protein 1B Impairs Urokinase Receptor Regeneration on the Cell Surface and Inhibits Cell Migration

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