References of "Noël, Agnès"
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See detailCellules Tumorales Circulantes : détection, caractérisation et intérêts cliniques
Gilles, Christine ULg; COLLIGNON, Joëlle ULg; Noël, Agnès ULg et al

in Revue Médicale de Liège (2011), 66(5-6), 279-84

The metastatic process generates circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in bone marrow and other organs which can remain as occult metastases. Various methods and systems have ... [more ▼]

The metastatic process generates circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in bone marrow and other organs which can remain as occult metastases. Various methods and systems have been developed to allow the isolation and identification of those cells but major technical limitations still exist. Research on CTCs is a nevertheless tremendously growing field of cancer research because of their potential clinical applications. CTCs indeed convey predictive information for the development of metastasis and recurrence, and prognostic information regarding patient survival. CTCs enumeration could also be used to monitor the effectiveness of adjuvant treatments. Moreover, enhancing our basic understanding of the metastatic process, CTCs, and DTCs in particular, are thought to contain subpopulations of cells with stem cells properties that would be responsible for relapses. [less ▲]

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See detailBiological aspects of angiogenesis in multiple myeloma.
Otjacques, Eléonore ULg; Binsfeld, Marilène ULg; Noël, Agnès ULg et al

in International Journal of Hematology (2011), 94(6), 505-18

Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant expansion of malignant plasma cells within the bone marrow (BM). One of the hallmarks of this disease is the close ... [more ▼]

Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant expansion of malignant plasma cells within the bone marrow (BM). One of the hallmarks of this disease is the close interaction between myeloma cells and neighboring cells within the BM. Angiogenesis, through the activation of endothelial cells, plays an essential role in MM biology. In the current review, we describe the angiogenesis process in MM by identifying the interacting cells, the pro- and anti-angiogenic cytokines modulated, and the extracellular matrix degrading proteases liable to participate in the pathophysiology. Finally, we highlight the impact of hypoxia (through hypoxia-inducible factor-1) and constitutive activation of nuclear factor-κB in this tumor-induced neo-vascularization. [less ▲]

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See detailCell cholesterol modulates metalloproteinase-dependent shedding of low-density lipoprotein receptor-related protein-1 (LRP-1) and clearance function.
Selvais, C.; D'Auria, L.; Tyteca, D. et al

in FASEB Journal (2011), 25(8), 2770-2781

Low-density lipoprotein receptor-related protein-1 (LRP-1) is a plasma membrane scavenger and signaling receptor, composed of a large ligand-binding subunit (515-kDa α-chain) linked to a shorter ... [more ▼]

Low-density lipoprotein receptor-related protein-1 (LRP-1) is a plasma membrane scavenger and signaling receptor, composed of a large ligand-binding subunit (515-kDa α-chain) linked to a shorter transmembrane subunit (85-kDa β-chain). LRP-1 cell-surface level and function are controlled by proteolytic shedding of its ectodomain. Here, we identified ectodomain sheddases in human HT1080 cells and demonstrated regulation of the cleavage by cholesterol by comparing the classical fibroblastoid type with a spontaneous epithelioid variant, enriched ∼2-fold in cholesterol. Two membrane-associated metalloproteinases were involved in LRP-1 shedding: a disintegrin and metalloproteinase-12 (ADAM-12) and membrane-type 1 matrix metalloproteinase (MT1-MMP). Although both variants expressed similar levels of LRP-1, ADAM-12, MT1-MMP, and specific tissue inhibitor of metalloproteinases-2 (TIMP-2), LRP-1 shedding from epithelioid cells was ∼4-fold lower than from fibroblastoid cells. Release of the ectodomain was triggered by cholesterol depletion in epithelioid cells and impaired by cholesterol overload in fibroblastoid cells. Modulation of LRP-1 shedding on clearance was reflected by accumulation of gelatinases (MMP-2 and MMP-9) in the medium. We conclude that cholesterol exerts an important control on LRP-1 levels and function at the plasma membrane by modulating shedding of its ectodomain, and therefore represents a novel regulator of extracellular proteolytic activities.-Selvais, C., D'Auria, L., Tyteca, D., Perrot, G, Lemoine, P., Troeberg, L., Dedieu, S., Noël, A., Nagase, H., Henriet, P., Courtoy, P. J., Marbaix, E., Emonard, H. Cell cholesterol modulates metalloproteinase-dependent shedding of low-density lipoprotein receptor-related protein-1 (LRP-1) and clearance function. [less ▲]

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See detailPotential Therapeutic Target Discovery by 2D-DIGE Proteomic Analysis in Mouse Models of Asthma
QUESADA CALVO, Florence ULg; Fillet, Marianne ULg; Renaut, Jenny et al

in Journal of Proteome Research (2011), 10(9), 4291-4301

As asthma physiopathology is complex and not fully understood to date; it is expected that new key mediators are still to be unveiled in this disease. The main objective of this study was to discover ... [more ▼]

As asthma physiopathology is complex and not fully understood to date; it is expected that new key mediators are still to be unveiled in this disease. The main objective of this study was to discover potential new target proteins with a molecular weight >20 kDa by using two-dimensional differential in-gel electrophoresis (2D-DIGE) on lung parenchyma extracts from control or allergen-exposed mice (ovalbumin). Two different mouse models leading to the development of acute airway inflammation (5 days allergen exposure) and airway remodeling (10 weeks allergen exposure) were used. This experimental setting allowed the discrimination of 33 protein spots in the acute inflammation model and 31 spots in the remodeling model displaying a differential expression. Several proteins were then identified by MALDI-TOF/TOF MS. Among those differentially expressed proteins, PDIA6, GRP78, Annexin A6, hnRPA3, and Enolase display an increased expression in lung parenchyma from mice exposed to allergen for 5 days. Conversely, Apolipoprotein A1 was shown to be decreased after allergen exposure in the same model. Analysis on lung parenchyma of mice exposed to allergens for 10 weeks showed decreased calreticulin levels. Changes in the levels of those different mediators were confirmed by Western blot and immunohistochemical analysis. Interestingly, alveolar macrophages isolated from lungs in the acute inflammation model displayed enhanced levels of GRP78. Moreover, intratracheal instillation of anti-GRP78 siRNA in allergen-exposed animals led to a decrease in eosinophilic inflammation and bronchial hyperresponsiveness. This study unveils new mediators of potential importance that are up- and down-regulated in asthma. Among up-regulated mediators, GRP-78 appears as a potential new therapeutic target worthy of further investigations. [less ▲]

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See detailThe Pbx Interaction Motif of Hoxa1 Is Essential for Its Oncogenic Activity
Delval, Stéphanie; Taminiau, Arnaud; Lamy, Juliette et al

in PLoS ONE (2011), 6(9), 2547

Hoxa1 belongs to the Hox family of homeodomain transcription factors involved in patterning embryonic territories and governing organogenetic processes. In addition to its developmental functions, Hoxa1 ... [more ▼]

Hoxa1 belongs to the Hox family of homeodomain transcription factors involved in patterning embryonic territories and governing organogenetic processes. In addition to its developmental functions, Hoxa1 has been shown to be an oncogene and to be overexpressed in the mammary gland in response to a deregulation of the autocrine growth hormone. It has therefore been suggested that Hoxa1 plays a pivotal role in the process linking autocrine growth hormone misregulation and mammary carcinogenesis. Like most Hox proteins, Hoxa1 can interact with Pbx proteins. This interaction relies on a Hox hexapeptidic sequence centred on conserved Tryptophan and Methionine residues. To address the importance of the Hox-Pbx interaction for the oncogenic activity of Hoxa1, we characterized here the properties of a Hoxa1 variant with substituted residues in the hexapeptide and demonstrate that the Hoxa1 mutant lost its ability to stimulate cell proliferation, anchorage-independent cell growth, and loss of contact inhibition. Therefore, the hexapeptide motif of Hoxa1 is required to confer its oncogenic activity, supporting the view that this activity relies on the ability of Hoxa1 to interact with Pbx. [less ▲]

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See detailMicroRNA-21 Exhibits Antiangiogenic Function by Targeting RhoB Expression in Endothelial Cells.
Sabatel, Céline; Malvaux, Ludovic ULg; Bovy, Nicolas ULg et al

in PLoS ONE (2011), 6(2), 16979

BACKGROUND: MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that regulate gene expression at post-transcriptional level. The recent discovery of the involvement of these RNAs in the ... [more ▼]

BACKGROUND: MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that regulate gene expression at post-transcriptional level. The recent discovery of the involvement of these RNAs in the control of angiogenesis renders them very attractive in the development of new approaches for restoring the angiogenic balance. Whereas miRNA-21 has been demonstrated to be highly expressed in endothelial cells, the potential function of this miRNA in angiogenesis has never been investigated. METHODOLOGY/PRINCIPAL FINDINGS: We first observed in endothelial cells a negative regulation of miR-21 expression by serum and bFGF, two pro-angiogenic factors. Then using in vitro angiogenic assays, we observed that miR-21 acts as a negative modulator of angiogenesis. miR-21 overexpression reduced endothelial cell proliferation, migration and the ability of these cells to form tubes whereas miR-21 inhibition using a LNA-anti-miR led to opposite effects. Expression of miR-21 in endothelial cells also led to a reduction in the organization of actin into stress fibers, which may explain the decrease in cell migration. Further mechanistic studies showed that miR-21 targets RhoB, as revealed by a decrease in RhoB expression and activity in miR-21 overexpressing cells. RhoB silencing impairs endothelial cell migration and tubulogenesis, thus providing a possible mechanism for miR-21 to inhibit angiogenesis. Finally, the therapeutic potential of miR-21 as an angiogenesis inhibitor was demonstrated in vivo in a mouse model of choroidal neovascularization. CONCLUSIONS/SIGNIFICANCE: Our results identify miR-21 as a new angiogenesis inhibitor and suggest that inhibition of cell migration and tubulogenesis is mediated through repression of RhoB. [less ▲]

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See detailMir-146a : A new angiostatic miRNA with tumor-suppressive properties
Halkein, Julie ULg; Castermans, Karolien; Malvaux, Ludovic et al

Poster (2010, October)

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See detail16K human prolactin is an anti-lymphangiogenic factor in vitro and in vivo
Kinet, Virginie; Castermans, Karolien; Blacher, Silvia ULg et al

Poster (2010, May 21)

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See detailCancérologie
Lambert, Philippe; Noël, Agnès ULg; Coucke, Philippe ULg

Article for general public (2010)

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See detail16K human prolactin is an anti-lymphangiogenic factor in vitro and in vivo
Kinet, Virginie; Castermans, Karolien; Blacher, Silvia ULg et al

Poster (2010, March)

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See detailhCG: a pregnancy-related hormone stimulating angiogenesis and pericyte recruitment
Berndt, S; Blacher, Silvia ULg; Perrier d’Hauterive, S et al

Poster (2010)

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See detailNovel HDAC/DNMT twin inhibitors interfere with angiogenesis
Shiva Shankar, Thammadihalli Veerasangaiah ULg; Sulka, Béatrice; Blacher, Silvia ULg et al

Poster (2010)

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA ... [more ▼]

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent antiangiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, very little work has been done to understand the effect of this combination on normal and tumoral angiogenesis. We have designed and tested a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities in relevant models of angiogenesis in vitro (endothelial cells, pericytes and the 3D aortic ring assay) and in vivo (the chick chorioallantoic membrane assay). We have identified a lead compound having quantifiable antiangiogenic effect without cytotoxicity associated with increased global acetylation and decreased DNA methylation levels. This compound is presently used to develop effective approaches to treat cancer by modulating the process of angiogenesis. [less ▲]

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See detailRole of delta-like-4/Notch in the formation and wiring of the lymphatic network in zebrafish.
Geudens, I.; Herpers, R.; Hermans, K. et al

in Arteriosclerosis, Thrombosis, and Vascular Biology (2010), 30(9), 1695-702

OBJECTIVE: To study whether Notch signaling, which regulates cell fate decisions and vessel morphogenesis, controls lymphatic development. METHODS AND RESULTS: In zebrafish embryos, sprouts from the axial ... [more ▼]

OBJECTIVE: To study whether Notch signaling, which regulates cell fate decisions and vessel morphogenesis, controls lymphatic development. METHODS AND RESULTS: In zebrafish embryos, sprouts from the axial vein have lymphangiogenic potential because they give rise to the first lymphatics. Knockdown of delta-like-4 (Dll4) or its receptors Notch-1b or Notch-6 in zebrafish impaired lymphangiogenesis. Dll4/Notch silencing reduced the number of sprouts producing the string of parchordal lymphangioblasts; instead, sprouts connecting to the intersomitic vessels were formed. At a later phase, Notch silencing impaired navigation of lymphatic intersomitic vessels along their arterial templates. CONCLUSIONS: These studies imply critical roles for Notch signaling in the formation and wiring of the lymphatic network. [less ▲]

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See detailDoes plasminogen activator inhibitor-1 drive lymphangiogenesis?
Bruyere, Francoise; Melen-Lamalle, Laurence; Blacher, Silvia ULg et al

in PLoS ONE (2010), 5(3), 9653

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators ... [more ▼]

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and by regulating endothelial cell survival and migration. Protease system's role in lymphangiogenesis is unknown yet. Thus, based on its important pro-angiogenic effect, we hypothesized that PAI-1 may regulate lymphangiogenesis associated at least with metastatic dissemination of cancer cells. To address this issue, we studied the impact of PAI-1 deficiency in various murine models of tumoral lymphangiogenesis. Wild-type PAI-1 proficient mice were used as controls. We provide for the first time evidence that PAI-1 is dispensable for tumoral lymphangiogenesis associated with breast cancers either induced by mammary carcinoma cell injection or spontaneously appearing in transgenic mice expressing the polyomavirus middle T antigen (PymT) under the control of a mouse mammary tumor virus long-terminal repeat promoter (MMTV-LTR). We also investigated inflammation-related lymphatic vessel recruitment by using two inflammatory models. PAI-1 deficiency did neither affect the development of lymphangioma nor burn-induced corneal lymphangiogenesis. These novel data suggest that vascular remodelling associated with lymphangiogenesis and angiogenesis involve different molecular determinants. PAI-1 does not appear as a potential therapeutic target to counteract pathological lymphangiogenesis. [less ▲]

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See detailSoluble forms of VEGF receptor-1 and -2 promote vascular maturation via mural cell recruitment.
LORQUET, Sophie ULg; Berndt, Sarah; Blacher, Silvia ULg et al

in FASEB Journal (2010), 24(10), 3782-95

Two soluble forms of vascular endothelial growth factor (VEGF) receptors, sVEGFR-1 and sVEGFR-2, are physiologically released and overproduced in some pathologies. They are known to act as anti-VEGF ... [more ▼]

Two soluble forms of vascular endothelial growth factor (VEGF) receptors, sVEGFR-1 and sVEGFR-2, are physiologically released and overproduced in some pathologies. They are known to act as anti-VEGF agents. Here, we report that these soluble receptors contribute to vessel maturation by mediating a dialogue between endothelial cells (EC) and mural cells that leads to blood vessel stabilization. Through a multidisciplinary approach, we provide evidences that these soluble VEGF receptors promote mural cell migration through a paracrine mechanism involving interplay in EC between VEGF/VEGFR-2 and sphingosine-1- phosphate type-1 (S1P)/S1P1 pathways that leads to endothelial nitric oxyde synthase (eNOS) activation. This new paradigm is supported by the finding that sVEGFR-1 and -2: 1) induce an eNOS-dependent outgrowth of a mural cell network in an ex vivo model of angiogenesis, 2) increase the mural cell coverage of neovessels in vitro and in vivo, 3) promote mural cell migration towards EC, 4) stimulate endothelial S1P1 overproduction and eNOS activation that promote the migration and the recruitment of neighboring mural cells. These findings provide new insights into mechanisms regulating physiological and pathological angiogenesis and vessel stabilization. [less ▲]

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See detailHigher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis.
El Hour, Mehdi ULg; Moncada-Pazos, A.; Blacher, Silvia ULg et al

in Oncogene (2010), 29(20), 3025-32

ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) constitute a family of endopeptidases related to matrix metalloproteinases. These proteases have been largely implicated in ... [more ▼]

ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin motifs) constitute a family of endopeptidases related to matrix metalloproteinases. These proteases have been largely implicated in tissue remodeling and angiogenesis associated with physiological and pathological processes. To elucidate the in vivo functions of ADAMTS-12, we have generated a knockout mouse strain (Adamts12−/−) in which Adamts12 gene was deleted. The mutant mice had normal gestations and no apparent defects in growth, life span and fertility. By applying three different in vivo models of angiogenesis (malignant keratinocyte transplantation, Matrigel plug and aortic ring assays) to Adamts12−/− mice, we provide evidence for a protective effect of this host enzyme toward angiogenesis and cancer progression. In the absence of Adamts-12, both the angiogenic response and tumor invasion into host tissue were increased. Complementing results were obtained by using medium conditioned by cells overexpressing human ADAMTS-12, which inhibited vessel outgrowth in the aortic ring assay. This angioinhibitory effect of ADAMTS-12 was independent of its enzymatic activity as a mutated inactive form of the enzyme was similarly efficient in inhibiting endothelial cell sprouting in the aortic ring assay than the wild-type form. Altogether, our results show that ADAMTS-12 displays antiangiogenic properties and protect the host toward tumor progression. [less ▲]

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See detailLymphangiogenesis: in vitro and in vivo models
Bruyère, Françoise; Noël, Agnès ULg

in FASEB Journal (2010), 24(1), 8-21

Lymphangiogenesis, the formation of new lymphatic vessels from preexisting ones, is an important biological process associated with diverse pathologies, such as metastatic dissemination and graft ... [more ▼]

Lymphangiogenesis, the formation of new lymphatic vessels from preexisting ones, is an important biological process associated with diverse pathologies, such as metastatic dissemination and graft rejection. In addition, lymphatic hypoplasia characterizes lymphedema, usually a progressive and lifelong condition for which no curative treatment exists. Much progress has been made in recent years in identifying molecules specifically expressed on lymphatic vessels and in the setting up of in vitro and in vivo models of lymphangiogenesis. These new tools rapidly provided an abundance of information on the mechanisms underlying lymphatic development and the progression of diseases associated with lymphatic dysfunction. In this review, we describe the common in vitro and in vivo models of lymphangiogenesis that have proven suitable for investigating lymphatic biology and the interactions occurring between lymphatic vessels and other cells, such as immune cells and cancer cells. Their rationales and limitations are discussed and illustrated by the most informative findings obtained with them. [less ▲]

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See detailMembrane type 1 matrix metalloproteinase detection in tumors, using the iodinated endogenous [123I]-tissue inhibitor 2 of metalloproteinases as imaging agent.
Van Steenkiste, Magali; Oltenfreiter, Ruth; Frankenne, Francis et al

in Cancer Biotherapy & Radiopharmaceuticals (2010), 25(5), 511-20

Matrix metalloproteinases (MMPs) are principal participants in tumor development. In addition to serve as a useful biochemical marker, MMP expression may also provide a target for the diagnostic in vivo ... [more ▼]

Matrix metalloproteinases (MMPs) are principal participants in tumor development. In addition to serve as a useful biochemical marker, MMP expression may also provide a target for the diagnostic in vivo imaging of tumors, using a radiolabeled inhibitor. This study investigates the use of membrane type 1 (MT1)-MMP as target for in vivo tumor diagnosis. Specific binding of the endogenous tissue inhibitor of metalloproteinase-2 (TIMP-2) to MT1-MMP has been previously described. In this study, biodistribution and imaging experiments were performed on MT1-MMP-overexpressing (S.1.5) and control (C.IV.3) tumor-inoculated mice using [(123)I]-recombinant human TIMP-2 (rhTIMP-2) as radioligand and [(123)I]-rhTIMP-1 as control. The expression profile was controlled in vitro and on tumor extracts. rhTIMP-2 as well as rhTIMP-1 were labeled using the Iodogen method and characterized. Biodistribution of [(123)I]-rhTIMP-2 showed a tumor uptake of 2.87% +/- 1.58% ID/g at 3 hours postinjection in S.1.5. Tumor values of [(123)I]-rhTIMP-1 and [(123)I]-rhTIMP-2 evaluated in S.1.5 and C.IV.3, respectively, were significantly lower. Planar imaging revealed significant uptake of [(123)I]-rhTIMP-2 in S.1.5 compared with contralateral background areas. This could not be observed in C.IV.3 and with [(123)I]-rhTIMP-1 in S.1.5. All tumors were well established (200-800 mg). These results suggest that rhTIMP-2 holds potential for development of radiotracers for in vivo imaging in overexpressing MT1-MMP but not in similar tumors that do not express this protease. [less ▲]

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See detailTIMP-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in cancer cells
Sounni, Nor Eddine ULg; Rozanov, D. V.; Remacle, A. G. et al

in International Journal of Cancer = Journal International du Cancer (2010), 126(5), 1067-78

Both invasion-promoting MT1-MMP and its physiological inhibitorTIMP-2 play a significant role in tumorigenesis and are identified in the most aggressive cancers. Despite its antiproteolytic effects in ... [more ▼]

Both invasion-promoting MT1-MMP and its physiological inhibitorTIMP-2 play a significant role in tumorigenesis and are identified in the most aggressive cancers. Despite its antiproteolytic effects in vitro, clinical data suggest that TIMP-2 expression is positively associated with tumor recurrence, thus emphasizing the wide-ranging role of TIMP-2 in malignancies. To shed light on this role of TIMP-2, we report that low concentrations of TIMP-2, by interacting with MT1-MMP (a specific membrane receptor of TIMP-2), induce the MEK/ERK signaling cascade in fibrosarcoma HT1080 cells which express MT1-MMP naturally. TIMP-2 binding with cell surface-associated MT1-MMP stimulates phosphorylation of MEK1/2, which is upstream of ERK1/2, and the ERK1/2 substrate p90RSK. Consistent with volumes of literature, we confirmed that the activation of ERK stimulated cell migration. Both the transcriptional silencing of MT1-MMP and the inhibition of MEK1/2 reversed the signaling effects of TIMP-2/MT1-MMP while the active site-targeting MMP inhibitor GM6001 did not. Our data suggest that both the interactions of TIMP-2 with MT1-MMP, which activate the pro-migratory ERK signaling cascade, and the conventional inhibition of MT1-MMP's catalytic activity by TIMP-2, play a role in the invasion-promoting function of MT1-MMP. The TIMP-2-induced stimulation of ERK signaling in cancer cells explains the direct, as opposed to the inverse, association of TIMP-2 expression with poor prognosis in cancer. [less ▲]

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