Transforming growth factor-beta-mediated mast cell migration depends on mitogen-activated protein kinase activity

Transforming growth factor-beta (TGF-beta) isoforms regulate numerous cellu lar 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 g rowth inhibition was obtained at 400 pM. Protein tyrosine kinase inhibitors completely inhibited TGF-beta1-mediated migration, without affecting the a ntimitogenic response. Smad2 was phosphorylated upon TGF-beta1 treatment, b oth in the absence and presence of genistein. The mitogen-induced extracell ular kinase (MEK) inhibitor. PD98059, blocked the migratory response withou t affecting growth inhibition. In contrast, the p38 MAP kinase inhibitor. S B203580, had no significant effect on either migration or growth inhibition , These results indicate that different signalling pathways mediate TGF-bet a1-induced migration and growth inhibition in HMC-1 cells, where the migrat ion involves MEK activity. (C) 2001 Elsevier Science Inc. All rights reserv ed.