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

Academic Article
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Overview

authors

  • Varsano, T.
  • Dong, M. Q.
  • Niesman, I.
  • Gacula, H.
  • Lou, X.
  • Ma, T.
  • Testa, J. R.
  • Yates III, John
  • Farquhar, M. G.

publication date

  • December 2006

journal

  • Molecular and Cellular Biology  Journal

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.

subject areas

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Carrier Proteins
  • Endosomes
  • Glutathione Transferase
  • Hemagglutinins
  • Histidine
  • Models, Biological
  • Molecular Sequence Data
  • Nerve Growth Factor
  • Neurons
  • Neuropeptides
  • PC12 Cells
  • Protein Structure, Tertiary
  • Protein Transport
  • Rats
  • Receptor, trkA
  • Recombinant Proteins
  • Signal Transduction
  • rab5 GTP-Binding Proteins
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Identity

PubMed Central ID

  • PMC1636811

International Standard Serial Number (ISSN)

  • 0270-7306

Digital Object Identifier (DOI)

  • 10.1128/mcb.00305-06

PubMed ID

  • 17015470
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Additional Document Info

start page

  • 8942

end page

  • 8952

volume

  • 26

issue

  • 23

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