GIPC is recruited by APPL to peripheral TrkA endosomes and regulates TrkA trafficking and signaling.

Abstract:

: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.

journal_name

Mol Cell Biol

authors

Varsano T,Dong MQ,Niesman I,Gacula H,Lou X,Ma T,Testa JR,Yates JR 3rd,Farquhar MG

doi

10.1128/MCB.00305-06

subject

Has Abstract

pub_date

2006-12-01 00:00:00

pages

8942-52

issue

23

eissn

0270-7306

issn

1098-5549

pii

MCB.00305-06

journal_volume

26

pub_type

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