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Human Molecular Genetics, 2002, Vol. 11, No. 23 2855-2866
© 2002 Oxford University Press

Novel membrane traffic steps regulate the exocytosis of the Menkes disease ATPase

Christian Cobbold1, Sreenivasan Ponnambalam2, Michael J. Francis3 and Anthony P. Monaco1,*

1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7BN, UK, 2School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK and 3Amersham Biosciences, Maynard Centre, Forest Farm, Whitchurch, Cardiff CF14 7YT, UK

Received June 27, 2002; Accepted August 19, 2002

The Menkes disease protein (ATP7A or MNK) is a P-type transmembrane ATPase that regulates translocation of cytosolic copper ions across intracellular membranes of compartments along the secretory pathway. In this study, we show that endogenous MNK in cultured cell lines is localized to the distal Golgi apparatus and translocates to the plasma membrane in response to exogenous copper ions. This transport event is not blocked by expression of a dominant-negative mutant protein kinase D, an enzyme implicated in regulating constitutive trafficking from the trans-Golgi network (TGN) to the plasma membrane, whereas constitutive transport of CD4 is inhibited. In contrast, protein kinase A inhibitors block copper-stimulated MNK delivery to the plasma membrane. Expression of constitutively active Rho GTPases such as Cdc42, Rac1 and RhoA reveals a requirement for Cdc42 in the trafficking of MNK, to the cell surface. Furthermore, overexpression of WASp inhibits anterograde transport of MNK, further supporting regulation by the Cdc42 GTPase. These findings define a novel step in TGN-to-plasma membrane traffic required to export MNK to the cell surface.

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


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