TGF beta 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 II TGF beta receptors internalize into endosomes containing the early endosomal protein EEA1. The extent of TGF beta-stimulated Smad2 phosphorylation, Smad2 nuclear translocation, and TGF beta-stimulated transcription correlated closely with the extent of internalization of the receptor. TGF beta 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 TGF beta-induced Smad2 nuclear translocation. These results indicate that traffic of the TGF beta receptor into the endosome enables TGF beta signaling, revealing a novel function for the endosome as a compartment specialized for the amplification of certain extracellular signals.
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000502:physiology*; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005799:Genes, Dominant / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism; D021381:Protein Transport; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012697:Serine Endopeptidases; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D013347:Subcellular Fractions; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D014168:Transferrin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000166:cytology; D033921:Vesicular Transport Proteins; D016335:Zinc Fingers
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D015534:Trans-Activators; D014168:Transferrin; D016212:Transforming Growth Factor beta; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; C116420:ZFYVE16 protein, human; D012697:Serine Endopeptidases; D034281:Dynamins; D011188:Potassium