Ctr2 regulates biogenesis of a cleaved form of mammalian Ctr1 metal transporter lacking the copper- and cisplatin-binding ecto-domain

Copper is essential for normal growth and development because it serves roles in catalysis, signaling, and structure. Cells acquire copper through the copper transporter 1 (Ctr1) protein, a copper transporter that localizes to the cell membrane and intracellular vesicles. Both copper and the anticancer drug cisplatin are imported by Ctr1 by virtue of an extracellular domain rich in metal-binding amino acids. In this report we demonstrate that a protein structurally related to Ctr1, called Ctr2, plays a role in the generation or stability of a truncated form of Ctr1 lacking a large portion of the extracellular domain. Retention of this domain in mice or cells lacking Ctr2 enhances copper and cisplatin uptake, thereby establishing Ctr2 as a regulator of Ctr1 function.