Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1

Michael J. Petris, Kathryn Smith, Jaekwon Lee, Dennis J. Thiele

Research output: Contribution to journalArticle

216 Citations (Scopus)

Abstract

Copper uptake at the plasma membrane and subsequent delivery to copper-dependent enzymes is essential for many cellular processes, including mitochondrial oxidative phosphorylation, free radical detoxification, pigmentation, neurotransmitter synthesis, and iron metabolism. However, intracellular levels of this nutrient must be controlled because it is potentially toxic in excess concentrations. The hCtr1 protein functions in high affinity copper uptake at the plasma membrane of human cells. In this study, we demonstrate that levels of the hCtr1 protein at the plasma membrane of HEK293 cells were reduced when cells were exposed to elevated copper. This decrease in surface hCtr1 levels was associated with an increased rate of endocytosis, and low micromolar concentrations of copper were sufficient to stimulate this process. Inhibitors of clathrin-dependent endocytosis prevented the trafficking of hCtr1 from the plasma membrane, and newly internalized hCtr1 and transferrin were co-localized. Significantly, elevated copper concentrations also resulted in the degradation of the hCtr1 protein. Our findings suggest that hCtr1-mediated copper uptake into mammalian cells is regulated by a post-translational mechanism involving copper-stimulated endocytosis and degradation of the transporter.

Original languageEnglish (US)
Pages (from-to)9639-9646
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number11
DOIs
StatePublished - Mar 14 2003

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Endocytosis
Copper
Degradation
Cell membranes
Cell Membrane
Cells
Detoxification
Clathrin
Proteins
HEK293 Cells
Poisons
Oxidative Phosphorylation
Pigmentation
Transferrin
Metabolism
Nutrients
Proteolysis
Free Radicals
Neurotransmitter Agents
Iron

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. / Petris, Michael J.; Smith, Kathryn; Lee, Jaekwon; Thiele, Dennis J.

In: Journal of Biological Chemistry, Vol. 278, No. 11, 14.03.2003, p. 9639-9646.

Research output: Contribution to journalArticle

Petris, Michael J. ; Smith, Kathryn ; Lee, Jaekwon ; Thiele, Dennis J. / Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 11. pp. 9639-9646.
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