TGFβ-induced focal complex formation in epithelial cells is mediated by activated ERK and JNK MAP kinases and is independent of Smad4
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Yukiko Imamichi
Abstract
Advanced malignancies often exhibit increased concentrations of transforming growth factor-β (TGFβ), which has been suggested to promote invasion and metastasis. While inhibition of epithelial cell proliferation in response to TGFβ is mainly mediated by the well-characterised Smad pathway, the molecular mechanism leading to TGFβ-induced invasiveness and metastasis are largely unknown. To elucidate these mechanisms, we compared TGFβ1 signalling in MCF-7 and the Smad4-negative MDA-MB-468 breast cancer cells. Both cell lines react to TGFβ1 treatment with decreased subcortical actin and increased numbers of focal contacts. TGFβ1-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 TGFβ and subsequently translocated into focal contacts. Inhibition of the TGFβ 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 TGFβ1-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 TGFβ1 and necessary for TGFβ-induced migration. Taken together, our study identifies a role of ERK and JNK activation and association of activated MAPKs with focal complexes in TGFβ1-induced cell migration in epithelial cells. These TGFβ-dependent processes were mediated independently of Smad4.
References
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Articles in the same Issue
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