期刊
BIOLOGICAL CHEMISTRY
卷 386, 期 3, 页码 225-236出版社
WALTER DE GRUYTER GMBH
DOI: 10.1515/BC.2005.028
关键词
epithelial dedifferentiation; extracellular signal-regulated kinase (ERK); focal complex formation; Rho-GTPases; signal transduction; transforming growth factor-beta (TGFP)
Advanced malignancies often exhibit increased concentrations of transforming growth factor-beta (TGF beta), which has been suggested to promote invasion and metastasis. While inhibition of epithelial cell proliferation in response to TGF beta is mainly mediated by the well-characterised Smad pathway, the molecular mechanism leading to TGF beta-induced invasiveness and metastasis are largely unknown. To elucidate these mechanisms, we compared TGF beta 1 signalling in MCF-7 and the Smad4-negative MDA-MB-468 breast cancer cells. Both cell lines react to TGF beta 1 treatment with decreased subcortical actin and increased numbers of focal contacts. TGF beta 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 beta and subsequently translocated into focal contacts. Inhibition of the TGF beta 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 beta 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 beta 1 and necessary for TGF beta-induced migration. Taken together, our study identifies a role of ERK and JINK activation and association of activated MAPKs with focal complexes in TGF beta 1-induced cell migration in epithelial cells. These TGF beta-dependent processes were mediated independently of Smad4.
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