TGFβ Receptor Internalization into EEA1-Enriched Early Endosomes: Role in Signaling to Smad2

• Published in: The Journal of cell biology 2002-09, Vol.158 (7), p.1239-1249
• Main Authors: Hayes, Susan, Chawla, Anil, Corvera, Silvia
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Binding Sites; Carrier Proteins - metabolism; Cell nucleus; Cells; COS Cells; Cricetinae; DNA-Binding Proteins - physiology; Dynamins - genetics; Dynamins - metabolism; Endosomes; Endosomes - metabolism; Fluorescent Antibody Technique; Genes, Dominant - physiology; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins - metabolism; Phosphorylation; Potassium; Potassium - metabolism; Protein Transport; Receptors; Receptors, Transforming Growth Factor beta - metabolism; Serine Endopeptidases; Signal Transduction - physiology; Smad2 Protein; Subcellular Fractions; Trans-Activators - physiology; Transfection; Transferrin - metabolism; Transferrins; Transforming Growth Factor beta - metabolism; Tumor Cells, Cultured - cytology; Vesicular Transport Proteins; Zinc Fingers
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200204088

Transforming growth factor (TGF)β 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 II TGFβ receptors internalize into endosomes containing the early endosomal protein EEA1. The extent of TGFβ-stimulated Smad2 phosphorylation, Smad2 nuclear translocation, and TGFβ-stimulated transcription correlated closely with the extent of internalization of the receptor. TGFβ 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 TGFβ-induced Smad2 nuclear translocation. These results indicate that traffic of the TGFβ receptor into the endosome enables TGFβ signaling, revealing a novel function for the endosome as a compartment specialized for the amplification of certain extracellular signals.