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, Luke T.; Jennings, Ian G.; Kemp, Bruce E.; Pearson, Richard B.; Robinson, Phillip J.; Camakaris, James

doi:10.1016/j.biocel.2009.06.008

Cited by 54 publications

(64 citation statements)

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“…In the present study, we further investigated the influence of copper on APP trafficking in both neuronal and polarized epithelial cell models using confocal fluorescence imaging techniques. Experiments were carried out in normal growth medium, and the concentration of copper used was based on our previous studies (32,45,46). Consistent with our previous finding (39), exposure of SH-SY5Y cells to 150 M CuCl 2 in serum containing growth medium also resulted in an increase of APP at the cell surface (as assessed by biotinylation) compared with untreated controls (supplemental Fig.…”

Section: Resultssupporting

confidence: 73%

“…Future investigations will focus on identifying the physiological function(s) affected by copper-responsive APP relocalization. We recently reported that copper-responsive ATP7A trafficking is regulated by kinase phosphorylation of specific serine residues in ATP7A, implicating a signal transduction pathway(s) (46). Similarly, copper activation of the phosphoinositol 3-kinase pathway (71,72,74) can result in altered glycogen synthase kinase-3-mediated phosphorylation of APP, which may then FIGURE 8.…”

Section: Discussionmentioning

confidence: 99%

“…Primary cortical neurons were incubated with copper in serum-free Neurobasal medium (Invitrogen), and therefore lower copper concentrations were used (5-20 M; 3 h). The copper concentrations chosen were based on previously published data (32,45,46) as well as taking into consideration the presence of serum in the growth medium, which contains copper-binding proteins that reduce the amount of bioavailable copper, necessitating the use of higher copper concentrations than in serum-free media (32).…”

Section: Methodsmentioning

confidence: 99%

“…Primary cortical neurons used in these experiments were incubated in defined neurobasal medium without serum. Due to the absence of copper-binding proteins present in serum, which reduce "available copper" for cells, lower copper concentrations were used (46). Primary cortical neurons were exposed to a range of copper concentrations (5-20 M) for 3 h. At copper concentrations of 5 M and greater, there was a change in the cellular localization of APP from a predominantly perinuclear localization to a wider distribution, specifically toward neurites (Fig.…”

Section: Copper Increases App Localization To Neurites In Neuronalmentioning

confidence: 99%

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Copper Promotes the Trafficking of the Amyloid Precursor Protein

Acevedo¹,

Hung

Dalziel³

et al. 2011

Journal of Biological Chemistry

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Accumulation of the amyloid ␤ peptide in the cortical and hippocampal regions of the brain is a major pathological feature of Alzheimer disease. Amyloid ␤ peptide is generated from the sequential protease cleavage of the amyloid precursor protein (APP). We reported previously that copper increases the level of APP at the cell surface. Here we report that copper, but not iron or zinc, promotes APP trafficking in cultured polarized epithelial cells and neuronal cells. In SH-SY5Y neuronal cells and primary cortical neurons, copper promoted a redistribution of APP from a perinuclear localization to a wider distribution, including neurites. Importantly, a change in APP localization was not attributed to an up-regulation of APP protein synthesis. Using live cell imaging and endocytosis assays, we found that copper promotes an increase in cell surface APP by increasing its exocytosis and reducing its endocytosis, respectively. This study identifies a novel mechanism by which copper regulates the localization and presumably the function of APP, which is of major significance for understanding the role of APP in copper homeostasis and the role of copper in Alzheimer disease. The neuropathology of Alzheimer disease (AD)3 includes the accumulation of extracellular plaques containing amyloid ␤ peptide (A␤) in the cortical and hippocampal regions of the brain, intracellular neurofibrillary tangles, and trace metal dyshomeostasis. The trace metals copper, zinc, and iron are significantly enriched in the amyloid plaques of AD patients compared with age-matched subjects (1, 2). Interaction between A␤ and copper or zinc promotes peptide oligomerization and aggregation, eventually leading to further amyloid deposition (3-7). In addition, A␤ is able to catalyze the reduction of Cu(II) and Fe(III), generating reactive oxygen species that contribute to the oxidative stress observed in the AD brain (8 -14). Paradoxically, there is evidence of copper deficiency in neighboring cells (15-18), compromising the activity of copper-dependent enzymes, such as cytochrome c-oxidase and copper/zinc-superoxide dismutase (SOD1), which are essential for cellular respiration and as antioxidant defense, respectively (19 -21). Restoration of copper balance using ionophores (22), such as clioquionol and PBT-2, has shown promising results in both animal and human trials (23)(24)(25)(26). A proposed mechanism of action of these drugs is to bind to extracellular copper and restore intracellular copper levels, hence correcting copper dyshomeostasis. Importantly, these ionophores are capable of reducing amyloid load and attenuate cognitive decline (23-26).Amyloid precursor protein (APP) is differentially processed by the ␣-, ␤-, and ␥-secretases in two alternative processing pathways, commonly referred to as the nonamyloidogenic and amyloidogenic pathways (supplemental Fig. S1). In the non-amyloidogenic pathway, APP is initially cleaved by an ␣-secretase that is predominantly localized to the plasma membrane (27, 28), generating an N-terminal ectodomain (s...

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Section: Resultssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Copper Increases App Localization To Neurites In Neuronalmentioning

confidence: 99%

See 2 more Smart Citations

Copper Promotes the Trafficking of the Amyloid Precursor Protein

Acevedo¹,

Hung

Dalziel³

et al. 2011

Journal of Biological Chemistry

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“…Phosphorylation of Ser1342 and Ser1469 is essential for copper-dependent trafficking from the TGN to the plasma membrane [127]. However, copperdependent trafficking per se is not affected by mutations in these sites, suggesting that these serines possibly regulate direction of trafficking.…”

Section: Regulation Of Copper Transport By Posttranslational Modificamentioning

confidence: 99%

Posttranslational regulation of copper transporters

Berghe

Klomp

2009

J Biol Inorg Chem

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Copper Metabolism,ATP7AandMenkes Disease

Pierson

Lutsenko

Tümer

2015

Encyclopedia of Life Sciences

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ATP7A is an ATP‐driven copper transport protein that plays an essential role in human health. ATP7A is critically involved in dietary copper uptake in the intestine. In addition, ATP7A delivers copper to numerous copper‐dependent enzymes within the secretory pathway and facilitates copper transfer to the brain. Inactivating mutations in ATP7A are associated with severe and often lethal pathologies, such as Menkes disease, occipital horn syndrome, and distal motor neuropathy. Genetic and biochemical studies have demonstrated that disease‐causing mutations disrupt ATP7A in many ways, including disruption of biosynthesis, impairment of stability, inactivation of copper transport activity and disturbance of trafficking behaviour. Cellular studies also indicate that ATP7A is a subject of complex regulation. Despite significant progress in the characterisation of ATP7A's function, cell‐specific regulation of this transporter remains poorly understood. Many aspects of pathologies caused by mutations in ATP7A require further in depth studies. Key Concepts Copper is the third most abundant trace element in the body, after iron and zinc, and it is required for normal function of important copper‐dependent enzymes. Copper deficiency is detrimental to the development and function of many organs especially the central nervous system. Precise regulation of intracellular copper levels is vitally important because, although essential, excess copper has detrimental effects on metabolism. Several transporter molecules and carrier proteins are involved in regulating copper homeostasis. ATP7A is a member of a large family of P‐type ATPases. These ATP‐utilising membrane proteins pump ions across cellular membranes against a concentration gradient. ATP7A is involved in the delivery of copper to cuproenzymes in the secretory pathway and in the export of surplus copper from cells. Genetic defects in ATP7A leads to the X‐linked recessive Menkes disease. Menkes disease is a multi‐systemic lethal disorder, marked by neurodegenerative symptoms and connective tissue manifestations. Most of the clinical features of Menkes disease can be explained by deficiency of various copper‐dependent enzymes. ATP7A mutations vary from single nucleotide changes to microscopically detectable chromosome abnormalities. Ultimate diagnostic proof of Menkes disease is the demonstration of the molecular defect in ATP7A . Menkes disease patients show progressive deterioration of brain function. Administration of copper‐histidine before brain damage may slow the disease progression and result in less severe neurological symptoms.

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

Cited by 54 publications

References 54 publications

Copper Promotes the Trafficking of the Amyloid Precursor Protein

Copper Promotes the Trafficking of the Amyloid Precursor Protein

Posttranslational regulation of copper transporters

Copper Metabolism,ATP7AandMenkes Disease

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