Kinase activity profiling of gram-negative pneumonia.

Abstract

Pneumonia is a severe disease with high morbidity and mortality. A major causative pathogen is the Gram-negative bacterium Klebsiella (K.) pneumoniae. Kinases play an integral role in the transduction of intracellular signaling cascades and regulate a diverse array of biological processes essential to immune cells. The current study explored signal transduction events during murine Gram-negative pneumonia using a systems biology approach. Kinase activity arrays enable the analysis of 1,024 consensus sequences of protein kinase substrates. Using a kinase activity array on whole lung lysates, cellular kinase activities were determined in a mouse model of K. pneumoniae pneumonia. Notable kinase activities also were validated with phospho-specific Western blots. On the basis of the profiling data, mitogen-activated protein kinase (MAPK) signaling via p42 mitogen-activated protein kinase (p42) and p38 mitogen-activated protein kinase (p38) and transforming growth factor β (TGFβ) activity were reduced during infection, whereas v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) activity generally was enhanced. AKT signaling was represented in both metabolic and inflammatory (mitogen-activated protein kinase kinase 2 [MKK], apoptosis signal-regulating kinase/mitogen-activated protein kinase kinase kinase 5 [ASK] and v-raf murine sarcoma viral oncogene homolog B1 [b-RAF]) context. This study reaffirms the importance of classic inflammation pathways, such as MAPK and TGFβ signaling and reveals less known involvement of glycogen synthase kinase 3β (GSK-3β), AKT and SRC signaling cassettes in pneumonia.

• Authors: Arie J Hoogendijk, Sander H Diks, Maikel P Peppelenbosch, Tom Van Der Poll, Catharina W Wieland
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 17 Issue 7-8 Pg. 741-7 ( 2011) ISSN: 1528-3658 [Electronic] England
• PMID: 21424109 (Publication Type: Journal Article)

Chemical References

• Chemokines
• Cytokines
• Transforming Growth Factor beta
• Phosphotransferases
• src-Family Kinases
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• p38 Mitogen-Activated Protein Kinases
• Glycogen Synthase Kinase 3

Topics

• Animals
• Blotting, Western
• Chemokines (metabolism)
• Cluster Analysis
• Cytokines (metabolism)
• Female
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Host-Pathogen Interactions
• Klebsiella Infections (enzymology, microbiology)
• Klebsiella pneumoniae (physiology)
• Lung (enzymology, metabolism, microbiology)
• MAP Kinase Signaling System
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Phosphorylation
• Phosphotransferases (classification, metabolism)
• Pneumonia, Bacterial (enzymology, microbiology)
• Proteomics (methods)
• Proto-Oncogene Proteins c-akt (metabolism)
• Transforming Growth Factor beta (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)
• src-Family Kinases (metabolism)