PMID- 12506110
OWN - NLM
STAT- MEDLINE
DCOM- 20030423
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 10
DP  - 2003 Mar 7
TI  - Defective activation of c-Src in cystic fibrosis airway epithelial cells results 
      in loss of tumor necrosis factor-alpha-induced gap junction regulation.
PG  - 8326-32
AB  - Tumor necrosis factor-alpha (TNF-alpha) signaling is central to the transmission 
      of the innate immune response and subsequent activation of the adaptive immune 
      system. The functioning of both systems is required for optimal clearance of 
      pathogens from the airways. In cystic fibrosis (CF), dysfunction of the CF 
      transmembrane conductance regulator (CFTR) is associated with recurrent pulmonary 
      infections despite an intense inflammatory and immune response. We reported 
      recently that TNF-alpha decreased gap junction connectivity in non-CF airway 
      cells, a mechanism that was absent in CF cells expressing the DeltaPhe-508 mutant 
      of CFTR. We have now identified the tyrosine kinase c-Src as a possible pathway 
      between the mediators of inflammation and the gap junction protein connexin43 
      (Cx43). Indeed, TNF-alpha increased the proportion of activated c-Src in non-CF 
      airway cells. Moreover, pharmacological antagonists and expression in non-CF 
      cells of a dominant negative construct of c-Src prevented Cx43 channel closure by 
      TNF-alpha. Finally, gap junction channel closure was prevented by expression of a 
      Cx43 mutant lacking tyrosine phosphorylation sites for c-Src. Additional 
      experiments showed that activation of c-Src was defective in CF airway cells but 
      rescued in CFTR-corrected CF cells. These data suggest that CFTR dysfunction is 
      associated with altered TNF-alpha signaling, resulting in the persistence of gap 
      junction connectivity in CF airway cells. We propose that altered regulation of 
      c-Src may contribute to the dysregulated inflammatory response that is 
      characteristic of the CF phenotype.
FAU - Huang, Song
AU  - Huang S
AD  - Laboratory of Clinical Investigation III, Department of Pediatrics, Geneva 
      University Hospitals, Switzerland.
FAU - Dudez, Tecla
AU  - Dudez T
FAU - Scerri, Isabelle
AU  - Scerri I
FAU - Thomas, Marc A
AU  - Thomas MA
FAU - Giepmans, Ben N G
AU  - Giepmans BN
FAU - Suter, Susanne
AU  - Suter S
FAU - Chanson, Marc
AU  - Chanson M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20021227
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins pp60(c-src))
SB  - IM
MH  - Cell Line
MH  - Cystic Fibrosis/*metabolism
MH  - Gap Junctions/*physiology
MH  - Humans
MH  - Proto-Oncogene Proteins pp60(c-src)/*metabolism
MH  - Trachea/metabolism
MH  - Tumor Necrosis Factor-alpha/*physiology
EDAT- 2002/12/31 04:00
MHDA- 2003/04/24 05:00
CRDT- 2002/12/31 04:00
PHST- 2002/12/31 04:00 [pubmed]
PHST- 2003/04/24 05:00 [medline]
PHST- 2002/12/31 04:00 [entrez]
AID - S0021-9258(20)86455-2 [pii]
AID - 10.1074/jbc.M208264200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Mar 7;278(10):8326-32. doi: 10.1074/jbc.M208264200. Epub 2002 
      Dec 27.