Melittin modulates keratinocyte function through P2 receptor-dependent ADAM activation.
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Melittin modulates keratinocyte function through P2 receptor-dependent ADAM activation. / Sommer, Anselm; Fries, Anja; Cornelsen, Isabell; Speck, Nancy; Koch Nolte, Friedrich; Gimpl, Gerald; Andrä, Jörg; Bhakdi, Sucharit; Reiss, Karina.
in: J BIOL CHEM, Jahrgang 287, Nr. 28, 28, 2012, S. 23678-23689.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Melittin modulates keratinocyte function through P2 receptor-dependent ADAM activation.
AU - Sommer, Anselm
AU - Fries, Anja
AU - Cornelsen, Isabell
AU - Speck, Nancy
AU - Koch Nolte, Friedrich
AU - Gimpl, Gerald
AU - Andrä, Jörg
AU - Bhakdi, Sucharit
AU - Reiss, Karina
PY - 2012
Y1 - 2012
N2 - Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-?, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent.
AB - Melittin, the major component of the bee venom, is an amphipathic, cationic peptide with a wide spectrum of biological properties that is being considered as an anti-inflammatory and anti-cancer agent. It modulates multiple cellular functions but the underlying mechanisms are not clearly understood. Here, we report that melittin activates disintegrin-like metalloproteases (ADAMs) and that downstream events likely contribute to the biological effects evoked by the peptide. Melittin stimulated the proteolysis of ADAM10 and ADAM17 substrates in human neutrophil granulocytes, endothelial cells and murine fibroblasts. In human HaCaT keratinocytes, melittin induced shedding of the adhesion molecule E-cadherin and release of TGF-?, which was accompanied by transactivation of the EGF receptor and ERK1/2 phosphorylation. This was followed by functional consequences such as increased keratinocyte proliferation and enhanced cell migration. Evidence is provided that ATP release and activation of purinergic P2 receptors are involved in melittin-induced ADAM activation. E-cadherin shedding and EGFR phosphorylation were dose-dependently reduced in the presence of ATPases or P2 receptor antagonists. The involvement of P2 receptors was underscored in experiments with HEK cells, which lack the P2X7 receptor and showed strikingly increased response to melittin stimulation after transfection with this receptor. Our study provides new insight into the mechanism of melittin function which should be of interest particularly in the context of its potential use as an anti-inflammatory or anti-cancer agent.
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Mice, Knockout
KW - Models, Biological
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Blotting, Western
KW - Cell Line
KW - Dose-Response Relationship, Drug
KW - HEK293 Cells
KW - Cadherins/metabolism
KW - Receptor, Epidermal Growth Factor/metabolism
KW - Extracellular Signal-Regulated MAP Kinases/metabolism
KW - Cell Survival/drug effects
KW - Adenosine Triphosphate/metabolism
KW - Membrane Proteins/genetics/metabolism
KW - Phosphorylation/drug effects
KW - Receptors, Purinergic P2X7/genetics/metabolism
KW - ADAM Proteins/genetics/metabolism
KW - Amyloid Precursor Protein Secretases/genetics/metabolism
KW - Embryo, Mammalian/cytology
KW - Fibroblasts/cytology/drug effects/metabolism
KW - Keratinocytes/cytology/drug effects/metabolism
KW - Melitten/pharmacology
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Mice, Knockout
KW - Models, Biological
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Blotting, Western
KW - Cell Line
KW - Dose-Response Relationship, Drug
KW - HEK293 Cells
KW - Cadherins/metabolism
KW - Receptor, Epidermal Growth Factor/metabolism
KW - Extracellular Signal-Regulated MAP Kinases/metabolism
KW - Cell Survival/drug effects
KW - Adenosine Triphosphate/metabolism
KW - Membrane Proteins/genetics/metabolism
KW - Phosphorylation/drug effects
KW - Receptors, Purinergic P2X7/genetics/metabolism
KW - ADAM Proteins/genetics/metabolism
KW - Amyloid Precursor Protein Secretases/genetics/metabolism
KW - Embryo, Mammalian/cytology
KW - Fibroblasts/cytology/drug effects/metabolism
KW - Keratinocytes/cytology/drug effects/metabolism
KW - Melitten/pharmacology
M3 - SCORING: Journal article
VL - 287
SP - 23678
EP - 23689
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 28
M1 - 28
ER -