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PMID:17704059

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Citation

Zigrino, P, Steiger, J, Fox, JW, Löffek, S, Schild, A, Nischt, R and Mauch, C (2007) Role of ADAM-9 disintegrin-cysteine-rich domains in human keratinocyte migration. J. Biol. Chem. 282:30785-93

Abstract

ADAM-9 belongs to a family of transmembrane, disintegrin-containing metalloproteinases involved in protein ectodomain shedding and cell-cell and cell-matrix interactions. The aim of this study was to analyze the expression of ADAM-9 in skin and to assess the role of this proteolytic/adhesive protein in skin physiology. In normal skin, ADAM-9 expression was detected in both the epidermis and dermis and in vitro in keratinocytes and fibroblasts. Here we report that ADAM-9 functions as a cell adhesion molecule via its disintegrin-cysteine-rich domain. Using solid phase binding assays and antibody inhibition experiments, we demonstrated that the recombinant disintegrin-cysteine-rich domain of ADAM-9 specifically interacts with the beta1 integrin subunit on keratinocytes. This was corroborated by co-immunoprecipitation. In addition, engagement of integrin receptors by the disintegrin-cysteine-rich domain resulted in ERK phosphorylation and increased MMP-9 synthesis. Treatment with the ERK inhibitor PD98059 inhibited MMP-9 induction. Furthermore, the presence of the soluble disintegrin-cysteine-rich domain did not interfere with cell migration on different substrates. However, keratinocytes adhering to the immobilized disintegrin-cysteine-rich domain showed increased motility, which was partially due to the induction of MMP-9 secretion. In summary, our results indicate that the ADAM-9 adhesive domain plays a role in regulating the motility of cells by interaction with beta1 integrins and modulates MMP synthesis.

Links

PubMed Online version:10.1074/jbc.M701658200

Keywords

ADAM Proteins/antagonists & inhibitors; ADAM Proteins/biosynthesis; ADAM Proteins/genetics; Antigens, CD29/genetics; Antigens, CD29/metabolism; Cell Adhesion/drug effects; Cell Adhesion/physiology; Cell Adhesion Molecules/antagonists & inhibitors; Cell Adhesion Molecules/biosynthesis; Cell Adhesion Molecules/genetics; Cell Line; Cell Movement/drug effects; Cell Movement/physiology; Dermis/cytology; Dermis/enzymology; Disintegrins/antagonists & inhibitors; Disintegrins/biosynthesis; Disintegrins/genetics; Epidermis/cytology; Epidermis/enzymology; Extracellular Signal-Regulated MAP Kinases/genetics; Extracellular Signal-Regulated MAP Kinases/metabolism; Flavonoids/pharmacology; Gene Expression Regulation, Enzymologic/physiology; Humans; Keratinocytes/cytology; Keratinocytes/enzymology; Matrix Metalloproteinase 9/biosynthesis; Matrix Metalloproteinase 9/genetics; Membrane Proteins/antagonists & inhibitors; Membrane Proteins/biosynthesis; Membrane Proteins/genetics; Phosphorylation/drug effects; Protein Structure, Tertiary/physiology; Skin Physiological Phenomena

Significance

Annotations

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

HUMAN:ITB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13443

F

Seeded From UniProt

complete

HUMAN:ITB1

involved_in

GO:0033631: cell-cell adhesion mediated by integrin

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FILA

involved_in

GO:0030216: keratinocyte differentiation

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM9

enables

GO:0005178: integrin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P05556

F

Seeded From UniProt

complete

HUMAN:ADAM9

involved_in

GO:0030216: keratinocyte differentiation

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM9

involved_in

GO:0033631: cell-cell adhesion mediated by integrin

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM9

involved_in

GO:0033627: cell adhesion mediated by integrin

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM9

involved_in

GO:0000186: activation of MAPKK activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM9

involved_in

GO:0007155: cell adhesion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM9

involved_in

GO:0051549: positive regulation of keratinocyte migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADAM9

involved_in

GO:0050714: positive regulation of protein secretion

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P14780)

Seeded From UniProt

complete

HUMAN:MMP9

involved_in

GO:0051549: positive regulation of keratinocyte migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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