Receptor endocytosis, once thought to be primarily a mechanism for terminating receptor signaling, is now known to be required for certain signals propagated by the epidermal growth factor receptor and some G protein-coupled receptors. Penheiter et al. examined the role of endocytosis in signaling from the transforming growth factor-β (TGF-β) receptor. The authors used incubation at low temperature, depletion of potassium, or expression of a dominant negative mutant of dynamin 2ab to inhibit endocytosis in mink lung epithelial cells. They found that phosphorylation of the activated type 1 TGF-β receptor and recruitment of SARA (Smad anchor for receptor activation) and Smad2 occurred normally in response to ligand binding, even when endocytosis was blocked. However, phosphorylation of Smad2, translocation of Smad 3 to the nucleus, and activation of gene transcription (which are all normally consequences of receptor activation) did not occur when endocytosis was inhibited. Thus the later events in Smad signaling appear to occur only after vesicles are pinched off from the membrane into endosomes.
S. G. Penheiter, H. Mitchell, N. Garamszegi, M. Edens, J. J. E. Doré Jr., E. B. Leof, Internalization-dependent and -independent requirements for transforming growth factor β receptor signaling via the Smad pathway. Mol. Cell. Biol. 22, 4750-4759 (2002). [Abstract] [Full Text]