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Molecular and Cellular Biology, December 2006, p. 8942-8952, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00305-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

GIPC Is Recruited by APPL to Peripheral TrkA Endosomes and Regulates TrkA Trafficking and Signaling

Tal Varsano,^1, Meng-Qiu Dong,^1,3, Ingrid Niesman,^1, Hyacynth Gacula,¹ Xiaojing Lou,¹ Tianlin Ma,² Joseph R. Testa,² John R. Yates III,³ and Marilyn G. Farquhar^1*

Department of Cellular and Molecular Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093,¹ Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,² Department of Cell Biology, Scripps Research Institute, La Jolla, California 92037³

Received 17 February 2006/ Returned for modification 28 March 2006/ Accepted 3 September 2006

GIPC is a PDZ protein located on peripheral endosomes that binds to the juxtamembrane region of the TrkA nerve growth factor (NGF) receptor and has been implicated in NGF signaling. We establish here that endogenous GIPC binds to the C terminus of APPL, a Rab5 binding protein, which is a marker for signaling endosomes. When PC12(615) cells are treated with either NGF or antibody agonists to activate TrkA, GIPC and APPL translocate from the cytoplasm and bind to incoming, endocytic vesicles carrying TrkA concentrated at the tips of the cell processes. GIPC, but not APPL, dissociates from these peripheral endosomes prior to or during their trafficking from the cell periphery to the juxtanuclear region, where they acquire EEA1. GIPC's interaction with APPL is essential for recruitment of GIPC to peripheral endosomes and for TrkA signaling, because a GIPC PDZ domain mutant that cannot bind APPL or APPL knockdown with small interfering RNA inhibits NGF-induced GIPC recruitment, mitogen-activated protein kinase activation, and neurite outgrowth. GIPC is also required for efficient endocytosis and trafficking of TrkA because depletion of GIPC slows down endocytosis and trafficking of TrkA and APPL to the early EEA1 endosomes in the juxtanuclear region. We conclude that GIPC, following its recruitment to TrkA by APPL, plays a key role in TrkA trafficking and signaling from endosomes.

Published ahead of print on 2 October 2006.

These three authors contributed equally to this work.

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