title: 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.
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.|Hughes Childhood Cancer Program, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: B Y
authors.initials: BY
authors.lastname: Ahn
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: R F G
authors.initials: RF
authors.lastname: Saldanha-Gama
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.|Hughes Childhood Cancer Program, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: J J
authors.initials: JJ
authors.lastname: Rahn
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.|Hughes Childhood Cancer Program, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Hao
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.|Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: N-H
authors.initials: NH
authors.lastname: Dang
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Alshehri
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.|Hughes Childhood Cancer Program, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: S M
authors.initials: SM
authors.lastname: Robbins
authors.affiliation: Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.|Hughes Childhood Cancer Program, University of Calgary, Calgary, Alberta, Canada.|Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
authors.forename: D L
authors.initials: DL
authors.lastname: Senger
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D005260:Female; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D054731:PDZ Domains / Q000235:genetics; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C484572:LDB2 protein, human; D060588:LIM Domain Proteins; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D017475:Receptors, Nerve Growth Factor; D014157:Transcription Factors; D017868:Cyclic AMP-Dependent Protein Kinases