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Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle : role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase

Conway, A M and Rakhit, S and Pyne, S and Pyne, N J (1999) Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle : role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase. Biochemical journal, 337 (2). pp. 171-177. ISSN 0264-6021

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Abstract

The mechanism used by the platelet-derived growth factor receptor (PDGFR) to activate the mitogen-activated- protein-kinase (p42/p44 MAPK) pathway was investigated in cultured airway smooth muscle (ASM) cells. We have found that pertussis toxin (PTX, which was used to inactivate the heterotrimeric G-protein Gi) induced an approx. 40-50% decrease in the activation of c-Src and p42/p44 MAPK by PDGF. An essential role for c-Src was confirmed using the c-Src inhibitor, PP1, which abolished p42/p44 MAPK activation (PP1 and PTX were without effect on PDGFR tyrosine phosphorylation). Furthermore, the PTX-dependent decrease in c-Src and p42/p44 MAPK activation appeared correlated. These findings suggest that the PDGFR can utilize the PTX-sensitive G-protein, Gi, to regulate c-Src and subsequent p42/p44 MAPK activation. Phosphoinositide 3-kinase (PI3K) has been shown by others to be involved in p42/p44 MAPK activation. This is confirmed here by experiments which showed that PI3K inhibitors (wortmannin and LY294002) reduced the activation of p42/p44 MAPK by PDGF. PI3K activity was increased in Grb-2 immunoprecipitates from PDGF-stimulated cells and was decreased by pretreating these cells with PTX. These findings show that Gi might also promote Grb-2-PI3K complex formation and that Grb-2 may be a site at which PI3K is integrated into the p42/p44 MAPK cascade. In conclusion, our results demonstrate that Gi enables the PDGFR to signal more efficiently to p42/p44 MAPK, and this appears to be achieved through the regulation of c-Src and Grb-2/PI3K, which are intermediates in the p42/p44 MAPK cascade.

Item type: Article
ID code: 34947
Keywords: adenosine diphosphate ribose, animals, calcium-calmodulin-dependent protein kinases, cells, cultured, enzyme activation, GTP-binding protein alpha subunits, Gi-Go, guinea pigs, mitogen-activated protein kinase 1, mitogen-activated protein kinase 3, mitogen-activated protein kinases, models, biological, muscle, smooth, pertussis toxin, phosphatidylinositol 3-kinases, phosphorylation, platelet-derived growth factor, receptors, platelet-derived growth factor, respiratory system, signal transduction, virulence factors, bordetella, src-family kinases, Pharmacy and materia medica, Biochemistry, Cell Biology, Molecular Biology
Subjects: Medicine > Pharmacy and materia medica
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Related URLs:
    Depositing user: Pure Administrator
    Date Deposited: 15 Nov 2011 16:06
    Last modified: 05 Sep 2014 12:35
    URI: http://strathprints.strath.ac.uk/id/eprint/34947

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