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DNAX-activating protein 10 (DAP10) membrane adaptor associates with receptor for advanced glycation end products (RAGE) and modulates the RAGE-triggered signaling pathway in human keratinocytes
- Source :
- Journal of Biological Chemistry. 289(34):23389-23402
- Publication Year :
- 2014
- Publisher :
- American Society for Biochemistry and Molecular, 2014.
-
Abstract
- The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of many inflammatory, degenerative, and hyperproliferative diseases, including cancer. Previously, we revealed mechanisms of downstream signaling from ligand-activated RAGE, which recruits TIRAP/MyD88. Here, we showed that DNAX-activating protein 10 (DAP10), a transmembrane adaptor protein, also binds to RAGE. By artificial oligomerization of RAGE alone or RAGE-DAP10, we found that RAGE-DAP10 heterodimer formation resulted in a marked enhancement of Akt activation, whereas homomultimeric interaction of RAGE led to activation of caspase 8. Normal human epidermal keratinocytes exposed to S100A8/A9, a ligand for RAGE, at a nanomolar concentration mimicked the pro-survival response of RAGE-DAP10 interaction, although at a micromolar concentration, the cells mimicked the pro-apoptotic response of RAGE-RAGE. In transformed epithelial cell lines, A431 and HaCaT, in which endogenous DAP10 was overexpressed, and S100A8/A9, even at a micromolar concentration, led to cell growth and survival due to RAGE-DAP10 interaction. Functional blocking of DAP10 in the cell lines abrogated the Akt phosphorylation from S100A8/A9-activated RAGE, eventually leading to an increase in apoptosis. Finally, S100A8/A9, RAGE, and DAP10 were overexpressed in the psoriatic epidermis. Our findings indicate that the functional interaction between RAGE and DAP10 coordinately regulates S100A8/A9-mediated survival and/or apoptotic response of keratinocytes.
- Subjects :
- TIRAP
Keratinocytes
medicine.medical_specialty
endocrine system diseases
Receptor for Advanced Glycation End Products
Biology
Caspase 8
Biochemistry
RAGE (receptor)
Internal medicine
medicine
Calgranulin B
Humans
Psoriasis
Calgranulin A
cardiovascular diseases
Receptors, Immunologic
Molecular Biology
Protein kinase B
Cells, Cultured
Cancer
Receptor for Advanced Glycation End Products (RAGE)
Cell growth
Signal transducing adaptor protein
nutritional and metabolic diseases
Cell Biology
Cell biology
Killer Cells, Natural
Endocrinology
medicine.anatomical_structure
cardiovascular system
RNA Interference
Signal transduction
Keratinocyte
human activities
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 00219258
- Volume :
- 289
- Issue :
- 34
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....cd774ada2db8e40f974c643a3db3d1c0