Phosphoinositide 3-kinase regulates the role of retromer in transcytosis of the polymeric immunoglobulin receptor
- Author(s): Vergés, Marcel
- Sebastián, Isabel
- Mostov, Keith E
- et al.
Published Web Locationhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WFC-4MDGP9N-1&_user=2929987&_coverDate=02%2F15%2F2007&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000053176&_version=1&_urlVersion=0&_userid=2929987&md5=5ad732ac56b8e8ec7cb0fef6a8febe94
Retromer is a multimeric protein complex that mediates intracellular receptor sorting. One of the roles of retromer is to promote transcytosis of the polymeric immunoglobulin receptor (pIgR) and its ligand polymeric immunoglobulin A (pIgA) in polarized epithelial cells. In Madin-Darby Canine Kidney (MDCK) cells, overexpression of Vps35, the retromer subunit key for cargo recognition, restores transcytosis to a pIgR mutant that is normally degraded. Here we show that pIgA transcytosis was not restored in these cells when treated with the specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Likewise, the decrease in pIgA transcytosis by wild-type pIgR seen upon PI3K inhibition was not reverted by Vps3S overexpression. PI3K inhibition reduced membrane association of sorting-nexins (SNX) 1 and 2, which constitute the retromer subcomplex involved in membrane deformation, while association of the Vps35-Vps26-Vps29 subcomplex, involved in cargo recognition, remained virtually unaffected. Colocalization between the two retromer subcomplexes was reduced upon the treatment. Whereas the interaction among the subunits of the Vps3S Vps26-Vps29 subcomplex remained unchanged, less Vps35 was found associated with pIgR upon P13K inhibition. In addition, colocalization of internalized pIgA with subunits of both retromer subcomplexes throughout the transcytotic pathway was substantially reduced by LY294002 treatment. These data implicate P13K in controlling retromer's role in pIgR-pIgA transcytosis. (c) 2006 Elsevier Inc. All rights reserved.
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