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  • The Menkes disease ATPase (ATP7A) is internalised via a Rac1-regulated, clathrin- and caveolae-independent pathway

    Author(s)
    Cobbold, C
    Coventry, J
    Ponnambalam, S
    Monaco, AP
    Griffith University Author(s)
    Cobbold, Christian J.
    Year published
    2003
    Metadata
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    Abstract
    The Menkes disease gene encodes a P-type transmembrane ATPase (MNK) that translocates cytosolic copper ions across intracellular membranes of compartments along the secretory pathway. MNK moves from the trans-Golgi network (TGN) to the cell surface in response to exogenously added copper ions and recycles back to the TGN upon copper removal. The protein contains a C-terminal di-leucine motif necessary for internalization from the cell surface. In this study we show that MNK is internalized by a novel pathway that is independent of clathrin-mediated endocytosis. Expression of dominant-negative mutants of the dynamin-I and ...
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    The Menkes disease gene encodes a P-type transmembrane ATPase (MNK) that translocates cytosolic copper ions across intracellular membranes of compartments along the secretory pathway. MNK moves from the trans-Golgi network (TGN) to the cell surface in response to exogenously added copper ions and recycles back to the TGN upon copper removal. The protein contains a C-terminal di-leucine motif necessary for internalization from the cell surface. In this study we show that MNK is internalized by a novel pathway that is independent of clathrin-mediated endocytosis. Expression of dominant-negative mutants of the dynamin-I and dynamin-II proteins that block clathrindependent endocytosis of the transferrin receptor, do not inhibit internalization of endogenous MNK, or a CD8-MCF1 reporter molecule. Similarly, inhibitors of caveolae-mediated uptake do not affect MNK internalization whilst preventing uptake of PODIPY-ganglioside GM1, a caveolae marker. In contrast, expression of a constitutively active mutant of the Rac1 GTPase inhibits plasma membrane internalization of both the MNK and transferrin receptor transmembrane proteins. Potential downstream effectors of Rac1-regulated MNK internalization are also analyzed. These findings define a novel route required for MNK internalization and delivery to endosomes.
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    Journal Title
    Human Molecular Genetics
    Volume
    12
    Issue
    13
    Publisher URI
    http://hmg.oxfordjournals.org/
    DOI
    https://doi.org/10.1093/hmg/ddg166
    Subject
    Biological sciences
    Biomedical and clinical sciences
    Publication URI
    http://hdl.handle.net/10072/27902
    Collection
    • Journal articles

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