The endocytic fate of the transferrin receptor is regulated by c-Abl kinase

Hong Cao, Barbara Schroeder, Jing Chen, Micah B. Schott, Mark A Mc Niven

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Clathrin-mediated endocytosis of transferrin (Tf) and its cognate receptor (TfR1) is a central pathway supporting the uptake of trophic iron. It has generally been assumed that this is a constitutive process. However, we have reported that the non-receptor tyrosine kinase, Src, is activated by Tf to facilitate the internalization of the Tf-TfR1 ligand-receptor complex. As an extension of these findings, we have tested whether subsequent trafficking steps might be regulated by additional kinase-dependent cascades, and we observed a significant endocytic block by inhibiting c-Abl kinase by a variety of methods. Importantly, Tf internalization was reduced significantly in all of these cell models and could be restored by re-expression of WT c-Abl. Surprisingly, this attenuated Tf-TfR1 endocytosis was due to a substantial drop in both the surface and total cellular receptor levels. Additional studies with the LDL receptor showed a similar effect. Surprisingly, immunofluorescence microscopy of imatinib-treated cells revealed a marked colocalization of internalized TfR1 with late endosomes/lysosomes, whereas attenuating the lysosome function with several inhibitors reduced this receptor loss. Importantly, inhibition of c-Abl resulted in a striking redistribution of the chaperone Hsc70 from a diffuse cytosolic localization to an association with the TfR1 at the late endosome-lysosome. Pharmacological inhibition of Hsc70 ATPase activity in cultured cells by the drug VER155008 prevents this chaperone-receptor interaction, resulting in an accumulation of the TfR1 in the early endosome. Thus, inhibition of c-Abl minimizes receptor recycling pathways and results in chaperone-dependent trafficking of the TfR1 to the lysosome for degradation. These findings implicate a novel role for c-Abl and Hsc70 as an unexpected regulator of Hsc70-mediated transport of trophic receptor cargo between the early and late endosomal compartments.

Original languageEnglish (US)
Pages (from-to)16424-16437
Number of pages14
JournalJournal of Biological Chemistry
Volume291
Issue number32
DOIs
StatePublished - Aug 5 2016

Fingerprint

Transferrin Receptors
Transferrin
Lysosomes
Phosphotransferases
Endosomes
Endocytosis
Cells
Clathrin
src-Family Kinases
LDL Receptors
Fluorescence Microscopy
Adenosine Triphosphatases
Recycling
Cultured Cells
Microscopic examination
Iron
Association reactions
Pharmacology
Ligands
Degradation

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)
  • Molecular Biology
  • Cell Biology

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The endocytic fate of the transferrin receptor is regulated by c-Abl kinase. / Cao, Hong; Schroeder, Barbara; Chen, Jing; Schott, Micah B.; Mc Niven, Mark A.

In: Journal of Biological Chemistry, Vol. 291, No. 32, 05.08.2016, p. 16424-16437.

Research output: Contribution to journalArticle

Cao, Hong ; Schroeder, Barbara ; Chen, Jing ; Schott, Micah B. ; Mc Niven, Mark A. / The endocytic fate of the transferrin receptor is regulated by c-Abl kinase. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 32. pp. 16424-16437.
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