Transforming growth factor-beta-mediated mast cell migration depends on mitogen-activated protein kinase activity.
Transforming growth factor-beta (TGF-beta) isoforms regulate numerous cellular functions through binding to receptors with intrinsic serine/threonine kinase activity that transduce the intracellular signals via activation of Smad proteins. In this study, we examined the signalling pathways involved in TGF-beta1-mediated growth inhibition and migration in a human mast cell line, HMC-1. TGF-beta1 evoked optimal migration at 40 fM, whereas maximal growth inhibition was obtained at 400 pM. Protein tyrosine kinase inhibitors completely inhibited TGF-beta1-mediated migration, without affecting the antimitogenic response. Smad2 was phosphorylated upon TGF-beta1 treatment, both in the absence and presence of genistein. The mitogen-induced extracellular kinase (MEK) inhibitor, PD98059, blocked the migratory response without affecting growth inhibition. In contrast, the p38 MAP kinase inhibitor, SB203580, had no significant effect on either migration or growth inhibition. These results indicate that different signalling pathways mediate TGF-beta1-induced migration and growth inhibition in HMC-1 cells, where the migration involves MEK activity.
Olsson
N
N
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, S-751 85, Uppsala, Sweden
Piek
E
E
Sundström
M
M
ten Dijke
P
P
Nilsson
G
G
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human