Function of Liver Activation-Regulated Chemokine/CC Chemokine Ligand 20 Is Differently Affected by Cathepsin B and Cathepsin D Processing

Hasan, Lara; Mazzucchelli, Luca; Liebi, Mark; Lis, Maddalena; Hunger, Robert E.; Tester, Angus M.; Overall, Christopher M.; Wolf, Marlene

doi:10.4049/jimmunol.176.11.6512

Cited by 42 publications

(31 citation statements)

References 55 publications

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“…A C-terminal antimicrobial fragment of MIP-3␣ is actually formed due to proteolysis by cathepsin D (47). Thus, generation of such peptides requires proteolysis.…”

Section: Discussionmentioning

confidence: 99%

Native Thrombocidin-1 and Unfolded Thrombocidin-1 Exert Antimicrobial Activity via Distinct Structural Elements

Kwakman

Krijgsveld

Boer

et al. 2011

Journal of Biological Chemistry

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Background:The properties required for antimicrobial activity of chemokines are unclear. Results: Native thrombocidin-1 requires a three-dimensional positive patch for activity, but unfolded thrombocidin-1 is active through the N-terminal linear peptide regions. Conclusion: Native thrombocidin-1 and unfolded thrombocidin-1 exert activity via distinct structural elements. Significance: Folded and unfolded antimicrobial chemokines can exert activity through different structural elements.

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“…A C-terminal antimicrobial fragment of MIP-3␣ is actually formed due to proteolysis by cathepsin D (47). Thus, generation of such peptides requires proteolysis.…”

Section: Discussionmentioning

confidence: 99%

Native Thrombocidin-1 and Unfolded Thrombocidin-1 Exert Antimicrobial Activity via Distinct Structural Elements

Kwakman

Krijgsveld

Boer

et al. 2011

Journal of Biological Chemistry

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“…Recently, Cat D and Cat B were found in these cells. However, it was not yet known whether Cat S was present in these cells 30 . MDA-MB-231 cells showed highly invasive abilities 23 .…”

Section: Discussionmentioning

confidence: 99%

Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells

Tsai

Lee

Chang

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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Elevated cathepsin S (Cat S) level is correlated with higher migration ability in tumor cells. This study investigates the inhibitory effect of novel synthetic a-ketoamide compounds on cathepsin activity and cancer cell migration. The effect of several a-ketoamide compounds on the activity of recombinant cathepsins (Cat S, Cat L and Cat K) was examined. Two highly metastatic cancer cell lines were incubated with three Cat S-specific compounds (6n, 6w and 6r) to analyze their effect on cellular Cat S activity and cell migration. At a 100 nM concentration, compounds 6n, 6r and 6w effectively inhibited Cat S activity. Cat S activity and cell migration were significantly reduced in CL1-3 cells after treatment with either 6n or 6w at 5 mM. Similar results were also obtained when A2058 cells were treated with 6n. These results highlight the therapeutic potential of a-ketoamide compounds, especially 6n and 6w, to prevent or delay cancer metastasis.

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“…Cleavage of proteoglycan core protein also disrupts chemokine gradients formed by chemokine binding to the glycosaminoglycan side chains (13). A variety of proteases are thought to be involved in chemokine cleavage including CD13, also known as aminopeptidase N (14), CD26, also known as dipeptidylpeptidase IV (15,16), dipeptidylpeptidase-8 (16), neutrophil elastase (17), cathepsin G (18), cathepsins B and D (19), and the matrix metalloproteinases (MMPs) 2 (reviewed in Refs. 20 -22).…”

mentioning

confidence: 99%

Matrix Metalloproteinase Processing of CXCL11/I-TAC Results in Loss of Chemoattractant Activity and Altered Glycosaminoglycan Binding

Cox

Dean

Roberts

et al. 2008

Journal of Biological Chemistry

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The CXCR3 chemokine receptor regulates the migration of Th1 lymphocytes and responds to three ligands: CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC. We screened for potential regulation of T cell responses by matrix metalloproteinase (MMP) processing of these important chemokines. The most potent of the CXCR3 ligands, CXCL11, was identified by matrixassisted laser desorption ionization time-of-flight mass spectrometry as a substrate of the PMN-specific MMP-8, macrophage-specific MMP-12, and the general leukocyte MMP-9. The 73-amino acid residue CXCL11 is processed at both the amino and carboxyl termini to generate CXCL11-(5-73), -(5-63), and -(5-58) forms. NH 2 -terminal truncation results in loss of agonistic properties, as shown in calcium mobilization and chemotaxis experiments using CXCR3 transfectants and human T lymphocytes. Moreover, CXCL11-(5-73) is a CXCR3 antagonist and interestingly shows enhanced affinity to heparin. However, upon COOH-terminal truncation to position 58 there is loss of antagonist activity and heparin binding. Together this highlights an unexpected site for receptor interaction and that the carboxyl terminus is critical for glycosaminoglycan binding, an essential function for the formation of chemokine gradients in vivo. Hence, MMP activity might regulate CXCL11 tissue gradients in two ways. First, the potential of CXCL11-(5-73) to compete active CXCL11 from glycosaminoglycans might lead to the formation of an antagonistic haptotactic chemokine gradient. Second, upon further truncation, MMPs disperse the CXCL11 gradients in a novel way by proteolytic loss of a COOH-terminal GAG binding site. Hence, these results reveal potential new roles in down-regulating Th1 lymphocyte chemoattraction through MMP processing of CXCL11.Chemokines are a superfamily of low molecular weight chemotactic cytokines that function in directing the migration of leukocytes and other cell types in a multitude of processes including development, lymphocyte homing, inflammation, and wound repair (1). Chemokines form haptotactic gradients in vivo through associations with proteoglycan glycosaminoglycans (2). Upon interaction with 7-transmembrane G proteincoupled receptors, chemokines induce a chemotactic response. The expression and secretion of inducible chemokines is stimulated during infection or injury to promote rapid and efficient inflammatory and immune responses. Conversely, dampening of inflammation, a critical event in allowing tissue repair to continue unimpeded and in preventing excessive tissue damage and autoimmunity, is known to involve coordinated down-regulation of chemokine expression (3), receptor internalization (4), scavenger receptors (5), and proteolytic mechanisms of inactivation and conversion to antagonists (6).Specific and limited proteolysis, termed processing (7), of chemokines results in altered bioactivity with functional consequences such as increased or decreased receptor binding (8), conversion of an agonist to an antagonist (6, 9), shedding of membrane-anchored chemokines (10, 11),...

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Function of Liver Activation-Regulated Chemokine/CC Chemokine Ligand 20 Is Differently Affected by Cathepsin B and Cathepsin D Processing

Cited by 42 publications

References 55 publications

Native Thrombocidin-1 and Unfolded Thrombocidin-1 Exert Antimicrobial Activity via Distinct Structural Elements

Native Thrombocidin-1 and Unfolded Thrombocidin-1 Exert Antimicrobial Activity via Distinct Structural Elements

Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells

Matrix Metalloproteinase Processing of CXCL11/I-TAC Results in Loss of Chemoattractant Activity and Altered Glycosaminoglycan Binding

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