Glioma invasion mediated by the p75 neurotrophin receptor (p75NTR/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 p75NTR (aka CD271) as a mediator of glioma invasion. Herein, we provide evidence that preventing phosphorylation of p75NTR on S303 by pharmacological inhibition of PKA, or by a mutational strategy (S303G), cripples p75NTR-mediated glioma invasion resulting in serine phosphorylation within the C-terminal PDZ-binding motif (SPV) of p75NTR. Consistent with this, deletion (ΔSPV) or mutation (SPM) of the PDZ motif results in abrogation of p75NTR-mediated invasion. Using a peptide-based strategy, we identified PDLIM1 as a novel signaling adaptor for p75NTR and provide the first evidence for a regulated interaction via S425 phosphorylation. Importantly, PDLIM1 was shown to interact with p75NTR 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 p75NTR-mediated invasion. Collectively, these data demonstrate a requirement for a regulated interaction of p75NTR with PDLIM1 and suggest that targeting either the PDZ domain interactions and/or the phosphorylation of p75NTR by PKA could provide therapeutic strategies for patients with glioblastoma.

Exosomes Derived from Human Primary and Metastatic Colorectal Cancer Cells Contribute to Functional Heterogeneity of Activated Fibroblasts by Reprogramming Their Proteome

“…Although PDL1M1 does not affect the rate of proliferation, anchorage‐independent growth, or tumor growth, it interacts with actin cytoskeleton to promote invasive and metastatic behavior of breast cancer cells . Moreover, PDLIM1 interacts with neurotrophin receptor p75 NTR in highly invasive patient‐derived glioma stem cells/tumor‐initiating cells to support cancer cell invasion …”

Meta-analysis of gene expression studies in endometrial cancer identifies gene expression profiles associated with aggressive disease and patient outcome

“…Reduced expression of EPHB2 29 and PDLIM1 30 are reported to be indicators of poor prognosis of colorectal cancer. Both genes appear to exhibit tissue-specific effects, with upregulation of EPHB2 reported to be associated with poor breast cancer survival31 and elevated expression of PDLIM1 reported to promote metastatic processes in breast and glioma3233. C4BPA and NLRC3 , genes involved in immune processes, are reported to be dysregulated in pancreatic34 and colorectal cancer, respectively35.…”

PDLIM1 Stabilizes the E-Cadherin/β-Catenin Complex to Prevent Epithelial–Mesenchymal Transition and Metastatic Potential of Colorectal Cancer Cells

“…PDLIM1 is a cytoskeletal protein that is diffusely expressed in heart, muscle, and gastrointestinal tract tissues, whereas normal breast tissues show nondetectable or weak expression of PDLIM1 (18,19). Previous studies implicate PDLIM1 as a prometastasis factor in glioma and breast cancer (20,21). However, given the tissue specificity of PDLIM1, the role of PDLIM1 in different tumor types might vary accordingly.…”