Journal
GENES & DEVELOPMENT
Volume 14, Issue 20, Pages 2610-2622Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.181700
Keywords
Ras; Raf; TGF beta; SMAD; apoptosis
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c-Raf-1 is a major effector of Ras proteins, responsible for activation of the ERK MAP kinase pathway and a critical regulator of both normal growth and oncogenic transformation. Using an inducible form of Raf in MDCK cells, we have shown that sustained activation of Raf alone is able to induce the transition from an epithelial to a mesenchymal phenotype. Raf promoted invasive growth in collagen gels, a characteristic of malignant cells; this was dependent on the operation of an autocrine loop involving TGF beta, whose secretion was induced by Raf. TGF beta induced growth inhibition and apoptosis in normal MDCK cells: Activation of Raf led to inhibition of the ability of TGF beta to induce apoptosis but not growth retardation. ERK has been reported previously to inhibit TGF beta signaling via phosphorylation of the linker region of Smads, which prevents their translocation to the nucleus. However, we found no evidence in this system that ERK can significantly influence the function of Smad2, Smad3, and Smad4 at the level of nuclear translocation, DNA binding, or transcriptional activation. Instead, strong activation of Raf caused a broad protection of these cells from various apoptotic stimuli, allowing them to respond to TGF beta with increased invasiveness while avoiding cell death. The Raf-MAP kinase pathway thus synergizes with TGF beta in promoting malignancy but does not directly impair TGF beta -induced Smad signaling.
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