Smad4-independent TGF-beta signaling in tumor cell migration

Abstract

Transforming growth factor-beta (TGF-beta) belongs to a family of multifunctional growth factors that participates in the regulation of a variety of cellular activities. Beside induction of growth inhibition and differentiation of epithelial cells, TGF-beta has been shown to promote epithelial-mesenchymal transition in most epithelial tumors. While inhibition of epithelial cell proliferation in response to TGF-beta is mainly mediated by the well-characterized Smad pathway and subsequent inhibition of gene transcription, the molecular mechanism leading to TGF-beta-induced invasiveness and metastasis of epithelial tumors is less clear. Recent results from several groups suggest that the induction of tumorigenic activity by TGF-beta includes not only signaling by Smads, but also by Rho-GTPases and mitogen-activated protein kinases (MAP kinases). Activation of the MAP kinases extracellular signal-regulated kinases (ERK) 1 and 2 as well as c-jun N-terminal kinase (JNK) has been identified as important steps in TGF-beta-induced, Smad4-independent signal transduction in epithelial cells. Recent results identify a role of activated ERK and JNK and their association with focal complexes in TGF-beta-induced, Smad4-independent cell migration of breast carcinoma cells, and are reviewed here.