title: Intracellular and extracellular domains of protein tyrosine phosphatase PTPRZ-B differentially regulate glioma cell growth and motility.
abstract: Gliomas are primary brain tumors for which surgical resection and radiotherapy is difficult because of the diffuse infiltrative growth of the tumor into the brain parenchyma. For development of alternative, drug-based, therapies more insight in the molecular processes that steer this typical growth and morphodynamic behavior of glioma cells is needed. Protein tyrosine phosphatase PTPRZ-B is a transmembrane signaling molecule that is found to be strongly up-regulated in glioma specimens. We assessed the contribution of PTPRZ-B protein domains to tumor cell growth and migration, via lentiviral knock-down and over-expression using clinically relevant glioma xenografts and their derived cell models. PTPRZ-B knock-down resulted in reduced migration and proliferation of glioma cells in vitro and also inhibited tumor growth in vivo. Interestingly, expression of only the PTPRZ-B extracellular segment was sufficient to rescue the in vitro migratory phenotype that resulted from PTPRZ-B knock-down. In contrast, PTPRZ-B knock-down effects on proliferation could be reverted only after re-expression of PTPRZ-B variants that contained its C-terminal PDZ binding domain. Thus, distinct domains of PTPRZ-B are differentially required for migration and proliferation of glioma cells, respectively. PTPRZ-B signaling pathways therefore represent attractive therapeutic entry points to combat these tumors.
authors.affiliation: Department of Cell Biology , Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Annika M
authors.initials: AM
authors.lastname: Bourgonje
authors.affiliation: Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Navis
authors.affiliation: Department of Cell Biology , Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jan T G
authors.initials: JT
authors.lastname: Schepens
authors.affiliation: Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Kiek
authors.initials: K
authors.lastname: Verrijp
authors.affiliation: PamGene International BV, 's-Hertogenbosch, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Hovestad
authors.affiliation: PamGene International BV, 's-Hertogenbosch, The Netherlands.
authors.forename: Riet
authors.initials: R
authors.lastname: Hilhorst
authors.affiliation: Department of Neuroscience, Institut Pasteur, Paris, France.
authors.forename: Sheila
authors.initials: S
authors.lastname: Harroch
authors.affiliation: Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.affiliation: Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: William P J
authors.initials: WP
authors.lastname: Leenders
authors.affiliation: Department of Cell Biology , Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Wiljan J A J
authors.initials: WJ
authors.lastname: Hendriks
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010641:Phenotype; D017434:Protein Structure, Tertiary; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: C516895:PTPRZ1 protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5