Biphasic role of TGF-beta1 in signal transduction and crosstalk.
TGF-beta1 induces cell cycle activation in mouse embryonic fibroblasts by down regulation of p27(Kip1) 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-beta1-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-beta1 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-beta1 but not EGF in fibroblasts arrested in early G1 is suggestive of a role of PKA-Raf-1 interaction in TGF-beta1 induced delay of EGF-induced cell cycle kinetics. A model for TGF-beta1 induced translocation to the plasma membrane-associated Raf-1 is proposed. Reports that Rho-like GTPase activity is critical for the activation of TGF-beta1 downstream pathways raises the question as to whether Rho proteins are involved in these observed TGF-beta1-induced responses. Post-receptor signaling mechanisms for TGF-beta1 and cross-talk with PKA-mediated pathways are examined in an effort to explain the modulation by TGF-beta1 of mitogen-induced cell proliferation in mesenchymal cells.
Wenner
Charles E
CE
Department of Cell and Molecular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA.
Yan
Shaochun
S
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020239:Receptor Cross-Talk / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017868:Cyclic AMP-Dependent Protein Kinases