Carboxypeptidase cathepsin X mediates β2-integrin-dependent adhesion of differentiated U-937 cells

Obermajer, Nataša; Premzl, Aleš; Bergant, Tina; Turk, Boris; Kos, Janko

doi:10.1016/j.yexcr.2006.04.019

Cited by 70 publications

(57 citation statements)

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“…30 In agreement with our previous results, 16 inhibition of cathepsin X activity during the activation of PBMC impaired Mac-1 activation and spreading, and promoted aggregation via LFA-1. 31,32 The FRET experiment confirmed that cathepsin X activates LFA-1 receptor.…”

Section: Discussionsupporting

confidence: 91%

“…17 Whereas in U-937 pro-monocytes its localization was intracellular vesicular, in phorbol 12-myristate 13-acetate (PMA)-differentiated U-937 cells, cathepsin X was restricted predominantly to the cell membrane. 16 The binding of cathepsin X to cell surface heparan sulfate proteoglycans, known as partners of integrins in focal adhesion formations, and the integrin-binding motifs, present in pro-(RGD) and in mature forms (ECD) of cathepsin X further suggest a function this enzyme might have in cell signaling and adhesion.…”

Section: Discussionmentioning

confidence: 99%

“…16 Because of the extended functions of b 2 integrin receptors in cell signalling and activation, other roles of cathepsin X are to be expected. More than 30 years ago it was suggested that a macrophage 'catheptic' carboxypeptidase activity plays a role in T cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…27,28 In recent studies, it has been shown that the constitutive activity of Mac-1 on antigen-presenting cells inhibits antigen presentation and down-regulates T-cell activation, 15,29 presumably because of suppression of inflammatory cytokine release. 29 The antibodies directed against CD11/CD18 inactivate Mac-1 activity, 28 vice versa, the inhibition of cathepsin X by 2F12 mAb diminishes adhesion of monocytes through the Mac-1 receptor 16 and enhances T lymphocyte proliferation. Similarly, in a MLR, alloantigen-induced T-cell proliferation could be increased by Mac-1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Cysteine protease cathepsin X modulates immune response via activation of β₂ integrins

et al. 2008

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Summary Cathepsin X is a lysosomal, cysteine dependent carboxypeptidase. Its expression is restricted to cells of the immune system, suggesting a function related to the processes of inflammatory and immune responses. It has been shown to stimulate macrophage antigen‐1 (Mac‐1) receptor‐dependent adhesion and phagocytosis via interaction with integrin β2 subunit. Here its potential role in regulating lymphocyte proliferation via Mac‐1 and the other β2 integrin receptor, lymphocyte function‐associated antigen‐1 (LFA‐1) has been investigated. Cathepsin X has been shown to suppress proliferation of human peripheral blood mononuclear cells, by activation of Mac‐1, known as a suppressive factor for lymphocyte proliferation. On the other hand, co‐localization of cathepsin X and LFA‐1 supports the role of cathepsin X in regulating LFA‐1 activity, which enhances lymphocyte proliferation. As shown by fluorescence resonance energy transfer, using U‐937 and Jurkat cells transfected with αL‐mCFP and β2‐mYFP, recombinant cathepsin X directly activates LFA‐1. The activation was confirmed by increased binding of monoclonal antibody 24, recognizing active LFA‐1. We demonstrate that cathepsin X is involved in the regulation of two β2 integrin receptors, LFA‐1 and Mac‐1, which exhibit opposing roles in lymphocyte activation.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cysteine protease cathepsin X modulates immune response via activation of β₂ integrins

et al. 2008

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“…The protein and activity levels of CtsB induced by PMA were comparable to those of M-CSF Mfs. The levels of CtsX and the secretion of CtsX and S were also upregulated, but to a much lesser extent than for CtsB.Cathepsin X is localized in the perinuclear vesicles of U-937 Mos and is translocated to the plasma membrane upon differentiation [30]. As shown by flow cytometry the same phenomenon was observed for CtsX and CtsB also after embedding the cells in a 3D environment (Fig.…”

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confidence: 69%

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

et al. 2012

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IntroductionThe ability of macrophages (Mfs) to progress to specific tissues, increase matrix remodeling, and induce angiogenesis is essential for their normal physiological function [1,2]. In addition, tissue infiltration of Mfs is also involved in pathological processes such as chronic inflammation, atherosclerosis, neurodegenerative disorders, and cancer progression [3]. The presence of Mfs Correspondence: Dr. Bojana Mirković e-mail: bojana.mirkovic@ffa.uni-lj.si within tumors is generally a marker of poor prognosis since they enhance angiogenesis and metastasis [4]. Furthermore, tumorassociated Mfs are emerging as essential matrix-remodeling cells during tumor-cell invasion. They have been reported to be present at high frequency at the invasive front of the tumor, where the breakdown of extracellular matrix (ECM) occurs [5]. Therefore, there is a great need to specifically control tissue infiltration of Mfs by targeting Mf migration-related molecules [6]. * These authors contributed equally to the present work. Eur. J. Immunol. 2012. 42: 3429-3441 Mf migration has been studied extensively in two dimensions (2D) on artificial substrates; however, in vivo Mfs migrate through physiological and pathological tissue and interact with the surrounding three-dimensional (3D) ECM, including basement membrane, collagen-rich interstitial matrices, and dense tissues such as tumors. Cells of different origins and/or at different differentiation stages use distinct mechanisms of cell motility in the 3D environment. In the mesenchymal mode, cells wider than the matrix pore size degrade the matrix via proteolytic and force-based matrix remodeling, thus migrating in a "path-generating" manner, while amoeboid cells squeeze through pre-existing pores in a proteaseindependent fashion in a "path-finding" mode [7,8]. The first 3D migration studies performed on cells of the immune system suggested that these cells migrate in a protease-independent fashion [7,9]. In contrast, a recent study demonstrated that Mfs adapt their migration strategy depending on the architecture of the 3D environment. In this study, Mfs were found to use the amoeboid migration mode in fibrillar collagen I and the mesenchymal migration mode in dense substrates, such as Matrigel and gelled collagen I [10].The invasion of cancer cells is facilitated by ECM-degrading invadopodia [11]. Podosomes are structures functionally similar to the invadopodia that are found in Mfs, osteoclasts, and DCs [12,13]. During migration on 2D surfaces [14], dot or ringlike podosomes form at the ventral surface of the migrating cells where they establish direct contact with the substratum and are also involved in matrix degradation [11]. Structurally, podosomes comprise a concentrated core of F-actin and actin-regulatory proteins [14]. Surrounding the core is a ring region that contains scaffolding-, signaling-, and integrin-binding proteins, including the typical focal adhesion proteins vinculin, talin, paxillin, and FAK [15]. When Mfs migrate in a 3D environment (i.e., migra...

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Protease Inhibitors: Mechanisms

Farady¹,

Craik²

2008

Wiley Encyclopedia of Chemical Biology

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Relatively few design principles underlie the mechanisms of inhibition of a myriad range of protease inhibitors. Protease inhibitors tend to be competitive and to compete with substrate binding, either through direct competition or deformation of the protease active site. Although protein inhibitors can gain potency through the burial of a large surface area and specificity through contacts with specific exosites, small‐molecule inhibitors primarily gain potency through interactions with the catalytic machinery of the enzyme and specificity through interactions with the substrate binding sites. Incorporation of these design principles into chemical probes and drugs have improved greatly our ability to create potent and specific protease inhibitors.

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Carboxypeptidase cathepsin X mediates β2-integrin-dependent adhesion of differentiated U-937 cells

Cited by 70 publications

References 49 publications

Cysteine protease cathepsin X modulates immune response via activation of β₂ integrins

Cysteine protease cathepsin X modulates immune response via activation of β₂ integrins

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

Protease Inhibitors: Mechanisms

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Carboxypeptidase cathepsin X mediates β2-integrin-dependent adhesion of differentiated U-937 cells

Cited by 70 publications

References 49 publications

Cysteine protease cathepsin X modulates immune response via activation of β2 integrins

Cysteine protease cathepsin X modulates immune response via activation of β2 integrins

Three‐dimensional invasion of macrophages is mediated by cysteine cathepsins in protrusive podosomes

Protease Inhibitors: Mechanisms

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Cysteine protease cathepsin X modulates immune response via activation of β₂ integrins

Cysteine protease cathepsin X modulates immune response via activation of β₂ integrins