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

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.