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          Institute: MPI für molekulare Biomedizin     Collection: Yearbook 2013     Display Documents

ID: 648341.0, MPI für molekulare Biomedizin / Yearbook 2013
Regulation of PTEN activity by p38delta-PKD1 signaling in neutrophils confers inflammatory responses in the lung
Authors:Ittner, A.; Block, H.; Reichel, C. A.; Varjosalo, M.; Gehart, H.; Sumara, G.; Gstaiger, M.; Krombach, F.; Zarbock, A.; Ricci, R.
Date of Publication (YYYY-MM-DD):2012-11-19
Title of Journal:J Exp Med
Issue / Number:12
Start Page:2229
End Page:2246
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Despite their role in resolving inflammatory insults, neutrophils trigger inflammation-induced acute lung injury (ALI), culminating in acute respiratory distress syndrome (ARDS), a frequent complication with high mortality in humans. Molecular mechanisms underlying recruitment of neutrophils to sites of inflammation remain poorly understood. Here, we show that p38 MAP kinase p38delta is required for recruitment of neutrophils into inflammatory sites. Global and myeloid-restricted deletion of p38delta in mice results in decreased alveolar neutrophil accumulation and attenuation of ALI. p38delta counteracts the activity of its downstream target protein kinase D1 (PKD1) in neutrophils and myeloid-restricted inactivation of PKD1 leads to exacerbated lung inflammation. Importantly, p38delta and PKD1 conversely regulate PTEN activity in neutrophils, thereby controlling their extravasation and chemotaxis. PKD1 phosphorylates p85alpha to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration. Thus, aberrant p38delta-PKD1 signaling in neutrophils may underlie development of ALI and life-threatening ARDS in humans.
Free Keywords:Acute Lung Injury/*metabolism; Animals; Cell Line; DNA Primers/genetics; Histological Techniques; Immunoprecipitation; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Mitogen-Activated Protein Kinase 13/genetics/*metabolism; Neutrophils/*metabolism; PTEN Phosphohydrolase/*metabolism; Protein Kinase C/*metabolism; Real-Time Polymerase Chain Reaction; Signal Transduction/*physiology
External Publication Status:published
Document Type:Article
Communicated by:keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:%G eng
Identifiers:ISSN:1540-9538 (Electronic) 0022-1007 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/23129748 [ID No:2]
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