SIGNALING EVENTS INITIATED BY TRANSFORMING GROWTH FACTOR-BETA(1) THATREQUIRE G(I-ALPHA-1)

Transforming growth factor-beta1 (TGF-beta1) initiates a series of sig naling events leading to diverse cell type-specific effects on prolife ration and morphology. The multiple effects of TGF-beta1 are not due t o selective expression of receptor subtypes, but rather probably refle ct cell-specific expression of downstream components of the particular signaling system. To address this possibility and to identify specifi c signaling pathways activated by TGF-beta1, we attempted to restore c ell responsiveness to the cytokine by introducing various intracellula r signal transducers in NIH-3T3 fibroblasts, a cell line that is minim ally responsive to TGF-beta1. In NIH-3T3 fibroblasts stably transfecte d with G(ialpha1) cDNA, TGF-beta1 induced a reversible morphological t ransformation that was identical to the effect of this cytokine in ind icator cells such as AKR-2B fibroblasts. G(ialpha1) transfectants also exhibited mitogenic hyperresponsiveness to TGF-beta1. TGF-beta1 does not elicit these responses in control nontransfected fibroblasts or ce lls transfected with the guanine nucleotide-binding protein G(oalpha1) . The response to TGF-beta1 in G(ialpha1) transfectants is blocked by pertussis toxin and is lost in G(ialpha1) transfectants that have spon taneously reverted and no longer express G(ialpha1). These data indica te that the expression of the guanine nucleotide-binding protein G(ial pha1), normally absent in these cells, confers cell sensitivity to TGF -beta1.