Myelin suppresses axon regeneration by PIR-B/SHP-mediated inhibition of Trk activity

Yuki Fujita, Shota Endo, Toshiyuki Takai, Toshihide Yamashita

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

Paired immunoglobulin-like receptor B (PIR-B) partially mediates the regeneration-inhibiting effects of the myelin-derived protein Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). In this study, we report that inhibition of the PIR-B signaling cascades in neurons enhances axon regeneration in the central nervous system (CNS). Binding of MAG to PIR-B led to the association of PIR-B with tropomyosin receptor kinase (Trk) neurotrophin receptors. Src homology 2-containing protein tyrosine phosphatase (SHP)-1 and SHP-2, which were recruited to PIR-B upon MAG binding, functioned as Trk tyrosine phosphatases. Further, SHP-1 and SHP-2 inhibition reduced MAG-induced dephosphorylation of Trk receptors and abolished the inhibitory effect of MAG on neurite growth. Thus, PIR-B associated with Trk to downregulate basal and neurotrophin-regulated Trk activity through SHP-1/2 in neurons. Moreover, in vivo transfection of small interfering RNA (siRNA) for SHP-1 or SHP-2 induced axonal regeneration after optic nerve injury in mice. Our results thus identify a new molecular target to enhance regeneration of the injured CNS.

Original languageEnglish
Pages (from-to)1389-1401
Number of pages13
JournalEMBO Journal
Volume30
Issue number7
DOIs
Publication statusPublished - 2011 Apr 6

Keywords

  • Src homology 2-containing protein tyrosine phosphatase (SHP)
  • axon regeneration
  • myelin
  • paired immunoglobulin-like receptor B (PIR-B)
  • tropomyosin receptor kinase (Trk)

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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