Small GTPase Rab12 regulates constitutive degradation of transferrin receptor

Traffic. 2011 Oct;12(10):1432-43. doi: 10.1111/j.1600-0854.2011.01240.x. Epub 2011 Jul 29.


Transferrin receptor (TfR) is a well-characterized plasma membrane protein that travels between the plasma membrane and intracellular membrane compartments. Although TfR itself should undergo degradation, the same as other intracellular proteins, whether a specific TfR degradation pathway exists has never been investigated. In this study, we screened small GTPase Rab proteins, common regulators of membrane traffic in all eukaryotes, for proteins that are specifically involved in TfR degradation. We performed the screening by three sequential methods, i.e. colocalization of Rab with TfR, colocalization with lysosomes, and knockdown of Rab by specific small interfering RNA (siRNA), and succeeded in identifying Rab12, a previously uncharacterized Rab isoform, as a prime candidate among the 60 human or mouse Rabs screened. We showed that expression of a constitutive active mutant of Rab12 reduced the amount of TfR protein, whereas functional ablation of Rab12 by knockdown of either Rab12 itself or its upstream activator Dennd3 increased the amount of TfR protein. Interestingly, however, knockdown of Rab12 had no effect on the degradation of epidermal growth factor receptor (EGFR) protein, i.e. on a conventional degradation pathway. Our findings indicated that TfR is constitutively degraded by a Rab12-dependent pathway (presumably from recycling endosomes to lysosomes), which is independent of the conventional degradation pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Intracellular Membranes / metabolism
  • Mice
  • Models, Biological
  • Protein Transport
  • RNA, Small Interfering / genetics
  • Receptors, Transferrin / metabolism*
  • Spleen / metabolism
  • Transfection
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism
  • rab GTP-Binding Proteins / physiology*


  • RNA, Small Interfering
  • Receptors, Transferrin
  • Rab12 protein, human
  • rab12 protein, mouse
  • rab GTP-Binding Proteins