title: Netrin-1-induced activation of Notch signaling mediates glioblastoma cell invasion.
abstract: Glioblastoma multiforme is an aggressively invasive human brain cancer, which lacks effective treatment. The axonal guidance protein, netrin-1, is overexpressed in glioblastoma tumor biopsies. In Matrigel invasion assays we observed that experimental overexpression of netrin-1 increased cell invasiveness and its downregulation decreased invasiveness. Using tandem affinity purification and mass spectrometry protein identification we found that netrin-1 forms a complex with both Notch2 and Jagged1. Recombinant netrin-1 colocalized with Jagged1 and Notch2 at the cell surface and was also present in the intracellular vesicles with Jagged1, but not with Notch2. Netrin-1 activated Notch signaling and subsequent glioblastoma cell invasion. Interestingly, the recombinant central domain of netrin-1 counteracted the effects of the full-length netrin-1: it inhibited glioblastoma cell invasion and Notch activation by retaining the Notch signaling complex at the cell surface. This finding may give rise to therapeutic applications. These results reveal a new mechanism leading to glioblastoma cell invasion, in which netrin-1 activates Notch signaling.
authors.affiliation: Department of Pathology, The Haartman Institute, Translational Cancer Biology Research Program and Helsinki University Hospital, University of Helsinki, Finland.
authors.forename: Irene
authors.initials: I
authors.lastname: Ylivinkka
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Hu
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Ville
authors.initials: V
authors.lastname: Rantanen
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: Tuula A
authors.initials: TA
authors.lastname: Nyman
authors.forename: Jorma
authors.initials: J
authors.lastname: Keski-Oja
authors.forename: Marko
authors.initials: M
authors.lastname: Hyytiäinen
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000075388:Netrin-1; D017434:Protein Structure, Tertiary; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497764:NOTCH2 protein, human; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D051883:Receptor, Notch2; D011994:Recombinant Proteins; D000072099:Serrate-Jagged Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1