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Varsano T , Dong MQ , Niesman I , Gacula H , Lou X , Ma T , Testa JR , Yates JR 3rd , Farquhar MG
GIPC is recruited by APPL to Peripheral TrkA Endosomes and Regulates TrkA Trafficking and Signaling
Mol Cell Biol. 2006 Dec;26(23) :8942-52
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GIPC is a PDZ protein located on peripheral endosomes that binds to the juxtamembrane region of the TrkA 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 siRNA inhibits NGF-induced GIPC recruitment, MAP 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.
Ca 100768/ca/nci Dk 17780/dk/niddk Journal Article Research Support, N.I.H., Extramural United States