Phosphorylation regulates copper-responsive trafficking of the Menkes copper transporting P-type ATPase

Veldhuis, Nicholas A., Valova, Valentina A., Gaeth, Ann P., Palstra, Nickless, Hannan, Katherine M., Michell, Belinda J., Kelly, Leonard E., Jennings, Ian, Kemp, Bruce E., Pearson, Richard B., Robinson, Phillip J. and Camakaris, James (2009) Phosphorylation regulates copper-responsive trafficking of the Menkes copper transporting P-type ATPase. The International Journal of Biochemistry and Cell Biology, 41 12: 2403-2412. doi:10.1016/j.biocel.2009.06.008


Author Veldhuis, Nicholas A.
Valova, Valentina A.
Gaeth, Ann P.
Palstra, Nickless
Hannan, Katherine M.
Michell, Belinda J.
Kelly, Leonard E.
Jennings, Ian
Kemp, Bruce E.
Pearson, Richard B.
Robinson, Phillip J.
Camakaris, James
Title Phosphorylation regulates copper-responsive trafficking of the Menkes copper transporting P-type ATPase
Journal name The International Journal of Biochemistry and Cell Biology   Check publisher's open access policy
ISSN 1357-2725
1878-5875
Publication date 2009-12
Sub-type Article (original research)
DOI 10.1016/j.biocel.2009.06.008
Volume 41
Issue 12
Start page 2403
End page 2412
Total pages 10
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon
Language eng
Abstract The Menkes copper-translocating P-type ATPase (ATP7A) is a critical copper transport protein functioning in systemic copper absorption and supply of copper to cuproenzymes in the secretory pathway. Mutations in ATP7A can lead to the usually lethal Menkes disease. ATP7A function is regulated by copper-responsive trafficking between the trans-Golgi Network and the plasma membrane. We have previously reported basal and copper-responsive kinase phosphorylation of ATP7A but the specific phosphorylation sites had not been identified. As copper stimulates both trafficking and phosphorylation of ATP7A we aimed to identify all the specific phosphosites and to determine whether trafficking and phosphorylation are linked. We identified twenty in vivo phosphorylation sites in the human ATP7A and eight in hamster, all clustered within the N- and C-terminal cytosolic domains. Eight sites were copper-responsive and hence candidates for regulating copper-responsive trafficking or catalytic activity. Mutagenesis of the copper-responsive phosphorylation site Serine-1469 resulted in mislocalization of ATP7A in the presence of added copper in both polarized (Madin Darby canine kidney) and non-polarized (Chinese Hamster Ovary) cells, strongly suggesting that phosphorylation of specific serine residues is required for copper-responsive ATP7A trafficking to the plasma membrane. A constitutively phosphorylated site, Serine-1432, when mutated to alanine also resulted in mislocalization in the presence of added copper in polarized Madin Darby kidney cells. These studies demonstrate that phosphorylation of specific serine residues in ATP7A regulates its sub-cellular localization and hence function and will facilitate identification of the kinases and signaling pathways involved in regulating this pivotal copper transporter.
Keyword Copper
Menkes
MDCK
Phosphorylation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
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Created: Wed, 19 Oct 2011, 09:54:33 EST by Nick Palstra on behalf of Queensland Brain Institute