A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein

Juan Carlos Arévalo, Hiroko Yano, Kenneth K. Teng, Moses V. Chao

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

A major question in cell biology is how molecular specificity is achieved by different growth factor receptors that activate apparently identical signaling events. For the neurotrophin family, a distinguishing feature is the ability to maintain a prolonged duration of signal transduction. However, the mechanisms by which neurotrophin receptors assemble such a sustained signaling complex are not understood. Here we report that an unusual ankyrin-rich transmembrane protein (ARMS + kidins220) is closely associated with Trk receptor tyrosine kinases, and not the EGF receptor. This association requires interactions between transmembrane domains of Trk and ARMS. ARMS is rapidly tyrosine phosphorylated after binding of neurotrophins to Trk receptors and provides a docking site for the CrkL-C3G complex, resulting in Rap1-dependent sustained ERK activation. Accordingly, disruption of Trk-ARMS or the ARMS-CrkL interaction with dominant-negative ARMS mutants, or treatment with small interference RNA against ARMS substantially reduce neurotrophin-elicited signaling to ERK, but without any effect upon Ras or Akt activation. These findings suggest that ARMS acts as a major and neuronal-specific platform for prolonged MAP kinase signaling by neurotrophins.

Original languageEnglish
Pages (from-to)2358-2368
Number of pages11
JournalEMBO Journal
Volume23
Issue number12
DOIs
StatePublished - Jun 16 2004

Keywords

  • BDNF
  • Crk
  • NGF
  • Rap1
  • Signal transduction

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