Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes

doi:10.1083/jcb.200201063

Published 13 May 2002. doi:10.1083/jcb.200201063

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© The Rockefeller University Press, 0021-9525/2002/5/679 $5.00
The Journal of Cell Biology, Volume 157, Number 4, May 13, 2002 679-691

Article

Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes

Yufang Shao¹, Wendy Akmentin¹, Juan Jose Toledo-Aral¹, Julie Rosenbaum¹, Gregorio Valdez¹, John B. Cabot¹, Brian S. Hilbush² and Simon Halegoua¹

¹ Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794
² Digital Gene Technologies Inc., La Jolla, CA 92037

Address correspondence to Simon Halegoua, Dept. of Neurobiology and Behavior, Life Sciences Bldg. 052, SUNY at Stony Brook, Stony Brook, NY 11794-5230. Tel.: (631) 632-8736. Fax: (631) 632-9714. E-mail: simon.halegoua{at}sunysb.edu

Acentral tenet of nerve growth factor (NGF) action that is poorlyunderstood is its ability to mediate cytoplasmic signaling,through its receptor TrkA, that is initiated at the nerve terminaland conveyed to the soma. We identified an NGF-induced proteinthat we termed Pincher (pinocytic chaperone) that mediates endocytosisand trafficking of NGF and its receptor TrkA. In PC12 cells,overexpression of Pincher dramatically stimulated NGF-inducedendocytosis of TrkA, unexpectedly at sites of clathrin-independentmacropinocytosis within cell surface ruffles. Subsequently,a system of Pincher-containing tubules mediated the deliveryof NGF/TrkA-containing vesicles to cytoplasmic accumulations.These vesicles selectively and persistently mediated TrkA-erk5mitogen-activated protein kinase signaling. A dominant inhibitorymutant form of Pincher inhibited the NGF-induced endocytosisof TrkA, and selectively blocked TrkA-mediated cytoplasmic signalingof erk5, but not erk1/2, kinases. Our results indicate thatPincher mediates pinocytic endocytosis of functionally specializedNGF/TrkA endosomes with persistent signaling potential.

Key Words: neutrophin; membrane trafficking; signal transduction; EH domain; MAP kinase

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