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.