A novel role for the ATP7A copper transporter in cancer
[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Copper is a trace metal with a ready capacity to gain or donate electrons. This property is harnessed by numerous enzymes to perform vital functions in the body. In humans, copper is required for various biochemical processes, including cellular respiration, connective tissue development, iron transport and pigmentation. The same redox property that makes copper useful can also have deleterious effects if the proper balance is not maintained. Cellular copper homeostasis is maintained by several different proteins, including CTR1 (copper transporter 1), a high affinity copper importer, as well as ATP7A and ATP7B copper exporting ATPases. ATP7A controls the cellular export of copper and this function of ATP7A is largely regulated by its subcellular localization. Under low intracellular copper concentrations, ATP7A protein is localized to the TGN (trans-Golgi network), where it transports copper to newly synthesized cuproenzymes. Under elevated intracellular copper concentrations, ATP7A traffics to the plasma membrane, subsequently releasing its copper load by fusion with the plasma membrane. To maintain copper homeostasis, ATP7A undergoes constitutive trafficking between the TGN and the plasma membrane. Several key regions in the protein are required for its internalization and successful retrieval from the plasma membrane. Previous studies had shown that a single di-leucine motif in the cytoplasmic tail of ATP7A was required for its internalization. It is hypothesized that multiple di-leucines in the carboxy-terminus of ATP7A are involved in the internalization of the protein. The study presented in this thesis, identified a second di-leucine motif in ATP7A that is a bonafide sorting signal sequence required for internalization and maintaining the steady state localization of the protein. ... Taken together, these findings identify roles for the ATP7A copper transporter at the nexus of platinum-drug resistance, tumorigenesis and metastatic pathways, underscoring its potential as a therapeutic drug target at multiple stages of carcinogenesis.
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