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MBC in Press, published online ahead of print February 6, 2008
Mol. Biol. Cell 10.1091/mbc.E07-12-1239

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Submitted on December 12, 2007
Revised on January 9, 2008
Accepted on January 25, 2008

Phosphatidylinositol-4-Kinase Type II Alpha Contains an AP-3 Sorting Motif and a Kinase Domain that are both Required for Endosome Traffic

Branch Craige,*{dagger} Gloria Salazar,{dagger} and Victor Faundez{dagger}{ddagger}

*Graduate Program in Biochemistry, Cell, and Developmental Biology, {dagger}Department of Cell Biology, {ddagger}Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322

Monitoring Editor: Sandra Lemmon

The adaptor complex 3 (AP-3) targets membrane proteins from endosomes to lysosomes, lysosome-related organelles and synaptic vesicles. Phosphatidylinositol-4-kinase type II {alpha} (PI4KII{alpha}) is one of several proteins possessing catalytic domains that regulate AP-3-dependent sorting. Here we present evidence that PI4KII{alpha} uniquely behaves both as a membrane protein cargo as well as an enzymatic regulator of adaptor function. In fact, AP-3 and PI4KII{alpha} form a complex that requires a dileucine sorting motif present in PI4KII{alpha}. Mutagenesis of either the PI4KII{alpha} sorting motif or its kinase active site indicates that both are necessary to interact with AP-3 and properly localize PI4KII{alpha} to LAMP-1-positive endosomes. Similarly, both the kinase activity and the sorting signal present in PI4KII{alpha} are necessary to rescue endosomal PI4KII{alpha} siRNA-induced mutant phenotypes. We propose a mechanism whereby adaptors use canonical sorting motifs to selectively recruit a regulatory enzymatic activity to restricted membrane domains.

Address correspondence to: Victor Faundez (faundez{at}cellbio.emory.edu)






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