Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis

doi:10.1083/jcb.200108123

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Published 4 March 2002. doi:10.1083/jcb.200108123

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© The Rockefeller University Press, 0021-9525/2002/3/921 $5.00
The Journal of Cell Biology, Volume 156, Number 5, March 4, 2002 921-929

Article

Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis

Sean D. Conner and Sandra L. Schmid

The Scripps Research Institute, La Jolla, CA 92037

Address correspondence to Sandra L. Schmid, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: (858) 784-2311. Fax: (858) 784-9126. E-mail: slschmid{at}scripps.edu

The µ2 subunit of the AP2 complex is known to be phosphorylatedin vitro by a copurifying kinase, and it has been demonstratedrecently that µ2 phosphorylation is required for transferrinendocytosis (Olusanya, O., P.D. Andrews, J.R. Swedlow, and E.Smythe. 2001. Curr. Biol. 11:896–900). However, the identityof the endogenous kinase responsible for this phosphorylationis unknown. Here we identify and characterize a novel memberof the Prk/Ark family of serine/threonine kinases, adaptor-associatedkinase (AAK)1. We find that AAK1 copurifies with adaptor protein(AP)2 and that it directly binds the ear domain of ${alpha}$ -adaptinin vivo and in vitro. In neuronal cells, AAK1 is enriched atpresynaptic terminals, whereas in nonneuronal cells it colocalizeswith clathrin and AP2 in clathrin-coated pits and at the leadingedge of migrating cells. AAK1 specifically phosphorylates theµ subunit in vitro, and stage-specific assays for endocytosisshow that µ phosphorylation by AAK1 results in a decreasein AP2-stimulated transferrin internalization. Together, theseresults provide strong evidence that AAK1 is the endogenousµ2 kinase and plays a regulatory role in clathrin-mediatedendocytosis. These results also lend support to the idea thatclathrin-mediated endocytosis is controlled by cycles of phosphorylation/desphosphorylation.

Key Words: AAK1; AP2; clathrin; kinase; endocytosis

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