2. Academic Validation
  3. Glioma invasion mediated by the p75 neurotrophin receptor (p75(NTR)/CD271) requires regulated interaction with PDLIM1

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.
B Y Ahn 1 2 3,  R F G Saldanha-Gama 1 3 4,  J J Rahn 1 2 3,  X Hao 1 2 3,  J Zhang 1 4,  N-H Dang 1 3 4,  M Alshehri 1 3 4,  S M Robbins 1 2 3 4,  D L Senger 1 2 3 4
Affiliations

Affiliations

  • 1 Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
  • 2 Hughes Childhood Cancer Program, University of Calgary, Calgary, Alberta, Canada.
  • 3 Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
  • 4 Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
PMID: 26119933 DOI: 10.1038/onc.2015.199
Abstract

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.

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