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PMID:17548643

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Citation

Gómez-Gaviro, M, Domínguez-Luis, M, Canchado, J, Calafat, J, Janssen, H, Lara-Pezzi, E, Fourie, A, Tugores, A, Valenzuela-Fernández, A, Mollinedo, F, Sánchez-Madrid, F and Díaz-González, F (2007) Expression and regulation of the metalloproteinase ADAM-8 during human neutrophil pathophysiological activation and its catalytic activity on L-selectin shedding. J. Immunol. 178:8053-63

Abstract

A disintegrin and metalloproteinase domain (ADAM) proteins are a family of transmembrane glycoproteins with heterogeneous expression profiles and proteolytic, cell-adhesion, -fusion, and -signaling properties. One of its members, ADAM-8, is expressed by several cell types including neurons, osteoclasts, and leukocytes and, although it has been implicated in osteoclastogenesis and neurodegenerative processes, little is known about its role in immune cells. In this study, we show that ADAM-8 is constitutively present both on the cell surface and in intracellular granules of human neutrophils. Upon in vitro neutrophil activation, ADAM-8 was mobilized from the granules to the plasma membrane, where it was released through a metalloproteinase-dependent shedding mechanism. Adhesion of resting neutrophils to human endothelial cells also led to up-regulation of ADAM-8 surface expression. Neutrophils isolated from the synovial fluid of patients with active rheumatoid arthritis expressed higher amounts of ADAM-8 than neutrophils isolated from peripheral blood and the concentration of soluble ADAM-8 in synovial fluid directly correlated with the degree of joint inflammation. Remarkably, the presence of ADAM-8 both on the cell surface and in suspension increased the ectodomain shedding of membrane-bound L-selectin in mammalian cells. All these data support a potential relevant role for ADAM-8 in the function of neutrophils during inflammatory response.

Links

PubMed

Keywords

ADAM Proteins/analysis; ADAM Proteins/metabolism; Antibodies, Monoclonal/immunology; Arthritis, Rheumatoid/enzymology; Arthritis, Rheumatoid/immunology; Catalysis; Cell Adhesion; Cell Membrane/enzymology; Cytoplasmic Granules/enzymology; Endothelial Cells/immunology; Humans; L-Selectin/metabolism; Membrane Proteins/analysis; Membrane Proteins/metabolism; Metalloproteases/analysis; Metalloproteases/metabolism; Neutrophils/enzymology; Neutrophils/immunology; Protein Transport; Synovial Fluid/immunology; Up-Regulation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ADAM8

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P14151

F

Seeded From UniProt

complete

HUMAN:ADAM8

involved_in

GO:0022407: regulation of cell-cell adhesion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM8

located_in

GO:0070820: tertiary granule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ADAM8

located_in

GO:0042581: specific granule

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ADAM8

located_in

GO:0032127: dense core granule membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ADAM8

located_in

GO:0032010: phagolysosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ADAM8

involved_in

GO:0010954: positive regulation of protein processing

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM8

involved_in

GO:0006954: inflammatory response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM8

enables

GO:0008237: metallopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ADAM8

located_in

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ADAM8

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ADAM8

involved_in

GO:2000391: positive regulation of neutrophil extravasation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM8

involved_in

GO:0051044: positive regulation of membrane protein ectodomain proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM8

involved_in

GO:0050714: positive regulation of protein secretion

ECO:0000305: curator inference used in manual assertion

GO:0051044

P

Seeded From UniProt

complete

HUMAN:LYAM1

enables

GO:0002020: protease binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P78325

F

Seeded From UniProt

complete


See also

References

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