RRC ID 35154
Author Ylivinkka I, Hu Y, Chen P, Rantanen V, Hautaniemi S, Nyman TA, Keski-Oja J, Hyytiäinen M.
Title Netrin-1-induced activation of Notch signaling mediates glioblastoma cell invasion.
Journal J Cell Sci
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.
Volume 126(Pt 11)
Pages 2459-69
Published 2013-6-1
DOI 10.1242/jcs.120022
PII jcs.120022
PMID 23549787
MeSH Calcium-Binding Proteins / genetics Calcium-Binding Proteins / metabolism* Cell Line, Tumor Glioblastoma / drug therapy Glioblastoma / genetics Glioblastoma / metabolism* Glioblastoma / pathology Humans Intercellular Signaling Peptides and Proteins / genetics Intercellular Signaling Peptides and Proteins / metabolism* Jagged-1 Protein Membrane Proteins / genetics Membrane Proteins / metabolism* Neoplasm Invasiveness Nerve Growth Factors / genetics Nerve Growth Factors / metabolism* Nerve Growth Factors / pharmacology Netrin-1 Protein Structure, Tertiary Receptor, Notch2 / genetics Receptor, Notch2 / metabolism* Recombinant Proteins / genetics Recombinant Proteins / metabolism Recombinant Proteins / pharmacology Serrate-Jagged Proteins Signal Transduction* Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism* Tumor Suppressor Proteins / pharmacology
IF 4.573
Times Cited 13
DNA material pEF-BOSneoSE-mNotch2 RAMIC (RDB06772)