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Vol. 18, Issue 8, 2991-3001, August 2007

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Canonical Interaction of Cyclin G–associated Kinase with Adaptor Protein 1 Regulates Lysosomal Enzyme Sorting

Satoshi Kametaka^*, Kengo Moriyama^*,, Patricia V. Burgos^*, Evan Eisenberg, Lois E. Greene, Rafael Mattera^*, and Juan S. Bonifacino^*

*Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, and Laboratory of Cell Biology, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892

Submitted December 29, 2006; Revised May 1, 2007; Accepted May 21, 2007
Monitoring Editor: Sandra Lemmon

The adaptor protein 1 (AP1) complex is a heterotetramer that participates in cargo sorting into clathrin-coated vesicles at the trans-Golgi network (TGN) and endosomes. The subunit of AP1 possesses a C-terminal "ear" domain that recruits a cohort of accessory proteins through recognition of a shared canonical motif, G[PDE][LM] (where is an aromatic residue). The physiological relevance of these ear-motif interactions, however, remains to be demonstrated. Here we report that the cyclin G–associated kinase (GAK) has two sequences fitting this motif, FGPL and FGEF, which mediate binding to the AP1--ear domain in vitro. Mutation of both -ear–binding sequences or depletion of AP1- by RNA interference (RNAi) decreases the association of GAK with the TGN in vivo. Depletion of GAK by RNAi impairs the sorting of the acid hydrolase, cathepsin D, to lysosomes. Importantly, expression of RNAi-resistant GAK restores the lysosomal sorting of cathepsin D in cells depleted of endogenous GAK, whereas expression of a similar construct bearing mutations in both -ear–binding sequences fails to correct the sorting defect. Thus, interactions between the G[PDE][LM]-motif sequences in GAK and the AP1--ear domain are critical for the recruitment of GAK to the TGN and the function of GAK in lysosomal enzyme sorting.

Present address: New England Inflammation and Tissue Protection Institute, Bouve College of Health Sciences, 113 Mugar Health Sciences Building, 360 Huntington Avenue, Boston, MA 02115.

Address correspondence to: Juan S. Bonifacino (juan{at}helix.nih.gov).

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