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Human Molecular Genetics, 2003, Vol. 12, No. 13 1523-1533
DOI: 10.1093/hmg/ddg166
© 2003 Oxford University Press

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

Christian Cobbold1, Julie Coventry1, Sreenivasan Ponnambalam2 and Anthony P. Monaco1,*

1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford 0X3 7BN, UK and 2School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK

Received February 21, 2003; Accepted April 30, 2003

The Menkes disease gene encodes a P-type transmembrane ATPase (ATP7A) that translocates cytosolic copper ions across intracellular membranes of compartments along the secretory pathway. ATP7A 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 ATP7A is internalized by a novel pathway that is independent of clathrin-mediated endocytosis. Expression of dominant-negative mutants of the dynamin-I, dynamin-II and Eps15 proteins that block clathrin-dependent endocytosis of the transferrin receptor do not inhibit internalization of endogenous ATP7A, or an ATP7A reporter molecule (CD8-MCF1). Similarly, inhibitors of caveolae-mediated uptake do not affect ATP7A 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 ATP7A and transferrin receptor transmembrane proteins. These findings define a novel route required for ATP7A internalization and delivery to endosomes.

* To whom correspondence should be addressed. Tel: +44 1865287502; Fax: +44 1865287650; Email: anthony.monaco{at}well.ox.ac.uk


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