Glioma invasion mediated by the p75 neurotrophin receptor (p75NTR/CD271) requires regulated interaction with PDLIM1

• Published in: Oncogene Vol. 35; no. 11; pp. 1411 - 1422
• Main Authors: Ahn, B Y, Saldanha-Gama, R F G, Rahn, J J, Hao, X, Zhang, J, Dang, N-H, Alshehri, M, Robbins, S M, Senger, D L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.03.2016; Nature Publishing Group
• Subjects: 13; 631/67/1922; 64; 64/60; 96; 96/1; 96/109; 96/31; 96/35; Apoptosis; Cancer therapies; Cell Biology; Cell receptors; Development and progression; Drug targeting; Genetic aspects; Gliomas; Health aspects; Human Genetics; Innovations; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Original; original-article; Phosphorylation; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.199

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.