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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON

Ankyrin facilitates intracellular trafficking of ₁-Na⁺-K⁺-ATPase in polarized cells

¹Departments of Pathology and Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, and ²Department of Pediatrics and Developmental Biology, Cincinnati Children's Hospital, Cincinnati, Ohio

Submitted 25 May 2008 ; accepted in final form 30 August 2008

Defects in ankyrin underlie many hereditary disorders involving the mislocalization of membrane proteins. Such phenotypes are usually attributed to ankyrin's role in stabilizing a plasma membrane scaffold, but this assumption may not be accurate. We found in Madin-Darby canine kidney cells and in other cultured cells that the 25-residue ankyrin-binding sequence of ₁-Na⁺-K⁺-ATPase facilitates the entry of ₁,β₁-Na⁺-K⁺-ATPase into the secretory pathway and that replacement of the cytoplasmic domain of vesicular stomatitis virus G protein (VSV-G) with this ankyrin-binding sequence bestows ankyrin dependency on the endoplasmic reticulum (ER) to Golgi trafficking of VSV-G. Expression of the ankyrin-binding sequence of ₁-Na⁺-K⁺-ATPase alone as a soluble cytosolic peptide acts in trans to selectively block ER to Golgi transport of both wild-type ₁-Na⁺-K⁺-ATPase and a VSV-G fusion protein that includes the ankyrin-binding sequence, whereas the trafficking of other proteins remains unaffected. Similar phenotypes are also generated by small hairpin RNA-mediated knockdown of ankyrin R or the depletion of ankyrin in semipermeabilized cells. These data indicate that the adapter protein ankyrin acts not only at the plasma membrane but also early in the secretory pathway to facilitate the intracellular trafficking of ₁-Na⁺-K⁺-ATPase and presumably other selected proteins. This novel ankyrin-dependent assembly pathway suggests a mechanism whereby hereditary disorders of ankyrin may be manifested as diseases of membrane protein ER retention or mislocalization.

spectrin; membrane protein; endoplasmic reticulum retention; Golgi; cytoskeleton; disease; endoplasmic reticulum

This article has been cited by other articles:

				P. R. Stabach, I. Simonovic, M. A. Ranieri, M. S. Aboodi, T. A. Steitz, M. Simonovic, and J. S. Morrow The structure of the ankyrin-binding site of {beta}-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties Blood, May 28, 2009; 113(22): 5377 - 5384. [Abstract] [Full Text] [PDF]