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Regulation of phosphatidylinositol (PI) 3-kinase plays an important role in modulating cellular function. We have previously shown that transforming growth factor (TGF)-beta 1 inhibited epidermal growth factor (EGF)-induced human airway smooth muscle (hASM) cell proliferation and that PI 3-kinase activation is a necessary signaling event in mitogen-induced hASM cell growth. In this study, we postulated that TGF-beta 1 may modulate EGF-induced PI 3-kinase activation. To date, no study has examined the effects of TGF-beta 1 on PI 3-kinase activity. In cultured hASM cells, EGF induced a 5.7 +/- 1.2-fold activation of PI 3-kinase compared with diluent-treated cells. Although TGF-beta 1 alone did not alter PI 3-kinase activation, TGF-beta 1 markedly enhanced EGF-induced PI 3-kinase activity, with a 16.6 +/- 1.9-fold increase over control cells treated with diluent alone. EGF significantly increased the association of PI 3-kinase with tyrosine phosphorylated proteins, and TGF-beta 1 pretreatment before EGF stimulation apparently did not alter this association. Interestingly, TGF-beta 1 did not modulate EGF-induced p70 S6 kinase activity, which is important for the progression of cells from the G0 to the G1 phase of the cell cycle. Immunoprecipitation of type I and type II TGF-beta receptors showed that PI 3-kinase was associated with both type I and type II TGF-beta receptors. TGF-beta 1, however, enhanced PI 3-kinase activity associated with the type I TGF-beta receptor. Although in some cell types inhibition of PI 3-kinase and treatment of cells with TGF-beta 1 mediate apoptosis, cell cycle analysis and DNA ladder studies show that PI 3-kinase inhibition or stimulation of hASM cells with TGF-beta 1 did not induce myocyte apoptosis. Although the inhibitory effects of TGF-beta 1 on hASM cell growth are not mediated at the level of PI 3-kinase and p70 S6 kinase, we now show that activation of the TGF-beta 1 receptor modulates PI 3-kinase activity stimulated by growth factors in hASM cells.
http://linkedlifedata.com/resource/pubmed/chemical/Epidermal Growth Factor, http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins, http://linkedlifedata.com/resource/pubmed/chemical/Phosphotyrosine, http://linkedlifedata.com/resource/pubmed/chemical/Ribosomal Protein S6 Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta
pubmed-meshheading:9435577-Cell Division, pubmed-meshheading:9435577-Cells, Cultured, pubmed-meshheading:9435577-Enzyme Activation, pubmed-meshheading:9435577-Epidermal Growth Factor, pubmed-meshheading:9435577-Humans, pubmed-meshheading:9435577-Kinetics, pubmed-meshheading:9435577-Muscle, Smooth, pubmed-meshheading:9435577-Phosphatidylinositol 3-Kinases, pubmed-meshheading:9435577-Phosphoproteins, pubmed-meshheading:9435577-Phosphotyrosine, pubmed-meshheading:9435577-Respiratory System, pubmed-meshheading:9435577-Ribosomal Protein S6 Kinases, pubmed-meshheading:9435577-Transforming Growth Factor beta
TGF-beta 1 modulates EGF-stimulated phosphatidylinositol 3-kinase activity in human airway smooth muscle cells.
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't