TGFβ receptor internalization into EEA1-enriched early endosomes:: role in signaling to Smad2

Transforming growth factor (TGF)beta is an important physiological regulator of cellular growth and differentiation. It activates a receptor threonine/serine kinase that phosphorylates the transcription factor Smad2, which then translocates into the nucleus to trigger specific transcriptional events. Here we show that activated type I and 11 TGFbeta receptors internalize into endosomes containing the early endosomal protein EEA1. The extent of TGFbeta-stimulated Smad2 phosphorylation, Smad2 nuclear translocation, and TGFbeta-stimulated transcription correlated closely with the extent of internalization of the receptor. TGFbeta signaling also requires SARA (Smad anchor for receptor activation), a 135-kD polypeptide that contains a FYVE Zn++ finger motif. Here we show that SARA localizes to endosomes containing EEA1, and that disruption of this localization inhibits TGFbeta-induced Smad2 nuclear translocation. These results indicate that traffic of the TGFbeta receptor into the endosome enables TGFbeta signaling, revealing a novel function for the endosome as a compartment specialized for the amplification of certain extracellular signals.