Distinctive Mechanism for Sustained TGF-β Signaling and Growth Inhibition: MEK1 Activation-Dependent Stabilization of Type II TGF-β Receptors

There are multiple mechanisms by which cells evade TGF-beta-mediated growth inhibitory effects. In this report, we describe a novel mechanism by which cells become resistant to TGF-beta-mediated growth suppression. Although having all the components of the TGF-beta signaling pathway, different cell lines, RL, HaCaT, and BJAB, have different sensitivities toward TGF-beta-induced growth suppression. The TGF-beta resistance of RL, a B-cell lymphoma cell line, was due to ligand-induced downregulation of TGF-beta receptor II (T beta RII) and only transient TGF-beta induced nuclear translocation of Smad2 and Smad3. With low-dose phorbol 12-myristate 13-acetate (PMA) or anti-IgM treatment, TGF-beta sensitivity was restored by stabilizing T beta RII expression and sustaining TGF-beta signaling. The MEK inhibitor, U0126, blocked both PMA- and anti-IgM-induced upregulation of T beta RII. In HaCaT and BJAB, two TGF-beta-sensitive cell lines, which had higher basal levels of phospho-MEK and T beta RII compared with RL, U0126 induced downregulation of T beta RII and blocked subsequent TGF-beta signaling. Similar results were also obtained with normal B cells, where MEK1 inhibitor downregulated T beta RII and subsequent TGF-beta signaling. Constitutively active MEK1, but not constitutively active ERK2, induced upregulation of T beta RII. Furthermore, T beta RII physically interacted with the constitutively active MEK1, but not with wild-type MEK1, indicating involvement of active MEK1 in stabilizing T beta RII. Collectively, our data suggest a novel mechanism for MEK1 in regulating the sensitivity to TGF-beta signaling by stabilizing T beta RII. Mol Cancer Res; 9(1); 78-89. (C) 2010 AACR.