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Yukiko Imamichi, Oliver Waidmann, Ramona Hein, Pinelopi Eleftheriou, Klaudia Giehl, Andre Menke
TGF?-induced focal complex formation in epithelial cells is mediated by activated ERK and JNK MAP kinases and is independent of Smad4
Keywords: epithelial dedifferentiation, extracellular signal-regulated kinase (ERK), focal complex formation, Rho-GTPases, signal transduction, transforming growth factor-? (TGF?)
Advanced malignancies often exhibit increased concentrations of transforming growth factor-? (TGF?), which has been suggested to promote invasion and metastasis. While inhibition of epithelial cell proliferation in response to TGF? is mainly mediated by the well-characterised Smad pathway, the molecular mechanism leading to TGF?-induced invasiveness and metastasis are largely unknown. To elucidate these mechanisms, we compared TGF?1 signalling in MCF-7 and the Smad4-negative MDA-MB-468 breast cancer cells. Both cell lines react to TGF?1 treatment with decreased subcortical actin and increased numbers of focal contacts. TGF?1-induced cell migration was strongly dependent on the activation of extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK). These mitogen-activated protein kinases were phosphorylated in response to TGF? and subsequently translocated into focal contacts. Inhibition of the TGF? type I receptor ALK5 slightly reduced phosphorylation of ERK in MCF-7 cells, but neither inhibited phosphorylation of ERK in MDA-MB-468 cells nor TGF?1-induced migration of both cell lines. In contrast, ALK5 inhibition effectively blocked Smad2 phosphorylation. In addition to ERK and JNK, the monomeric GTPase RhoA was activated by TGF?1 and necessary for TGF?-induced migration. Taken together, our study identifies a role of ERK and JNK activation and association of activated MAPKs with focal complexes in TGF?1-induced cell migration in epithelial cells. These TGF?-dependent processes were mediated independently of Smad4.
Biological Chemistry, Walter de Gruyter
Print ISSN: 1431-6730
Volume: 386, 03/2005
Pages: 225 - 236