Glioma invasion mediated by the p75 neurotrophin receptor (p75(NTR)/CD271) requires regulated interaction with PDLIM1

Oncogene. 2016 Mar 17;35(11):1411-22. doi: 10.1038/onc.2015.199. Epub 2015 Jun 29.


The invasive nature of glioblastoma renders them incurable by current therapeutic interventions. Using a novel invasive human glioma model, we previously identified the neurotrophin receptor p75(NTR) (aka CD271) as a mediator of glioma invasion. Herein, we provide evidence that preventing phosphorylation of p75(NTR) on S303 by pharmacological inhibition of PKA, or by a mutational strategy (S303G), cripples p75(NTR)-mediated glioma invasion resulting in serine phosphorylation within the C-terminal PDZ-binding motif (SPV) of p75(NTR). Consistent with this, deletion (ΔSPV) or mutation (SPM) of the PDZ motif results in abrogation of p75(NTR)-mediated invasion. Using a peptide-based strategy, we identified PDLIM1 as a novel signaling adaptor for p75(NTR) and provide the first evidence for a regulated interaction via S425 phosphorylation. Importantly, PDLIM1 was shown to interact with p75(NTR) in highly invasive patient-derived glioma stem cells/tumor-initiating cells and shRNA knockdown of PDLIM1 in vitro and in vivo results in complete ablation of p75(NTR)-mediated invasion. Collectively, these data demonstrate a requirement for a regulated interaction of p75(NTR) with PDLIM1 and suggest that targeting either the PDZ domain interactions and/or the phosphorylation of p75(NTR) by PKA could provide therapeutic strategies for patients with glioblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Female
  • Glioblastoma / pathology*
  • Humans
  • LIM Domain Proteins / genetics*
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness / pathology
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • PDZ Domains / genetics
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, Nerve Growth Factor / genetics*
  • Receptors, Nerve Growth Factor / metabolism
  • Signal Transduction / physiology
  • Transcription Factors / genetics*


  • LDB2 protein, human
  • LIM Domain Proteins
  • NGFR protein, human
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Receptors, Nerve Growth Factor
  • Transcription Factors
  • Cyclic AMP-Dependent Protein Kinases