Biphasic role of TGF-β1 in signal transduction and crosstalk

Abstract

TGF-β1 induces cell cycle activation in mouse embryonic fibroblasts by down regulation of p27Kip1 but it can also induce delay of EGF-induced cell cycle activation in these cells under similar conditions. In an attempt to determine the basis for these responses, the study of early TGF-β1 -induced signal transduction pathways in the presence and absence of EGF was undertaken. It is proposed that a likely target for the inhibition by TGF-β1 of the early EGF-induced p42/p44 MAPK is at the c-Raf locus. The finding that the catalytic subunits of PKA are associated with Raf-1 within minutes following application of TGF-β1 but not EGF in fibroblasts arrested in early G1 is suggestive of a role of PKA-Raf-1 interaction in TGF-β1 induced delay of EGF-induced cell cycle kinetics. A model for TGF-β1 induced translocation to the plasma membrane-associated Raf-1 is proposed. Reports that Rho-like GTPase activity is critical for the activation of TGF-β1 downstream pathways raises the question as to whether Rho proteins are involved in these observed TGF-β1-induced responses. Post-receptor signaling mechanisms for TGFβ1 and cross-talk with PKA-mediated pathways are examined in an effort to explain the modulation by TGF-β1 of mitogen-induced cell proliferation in mesenchymal cells. © 2003 Wiley-Liss, Inc.