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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Cell Line, Tumor
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Glioblastoma / drug therapy
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Glioblastoma / genetics
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Glioblastoma / metabolism*
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Glioblastoma / pathology
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Jagged-1 Protein
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Neoplasm Invasiveness
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism*
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Nerve Growth Factors / pharmacology
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Netrin-1
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Protein Structure, Tertiary
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Receptor, Notch2 / genetics
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Receptor, Notch2 / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Serrate-Jagged Proteins
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Signal Transduction*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Tumor Suppressor Proteins / pharmacology
Substances
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Calcium-Binding Proteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jagged-1 Protein
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Membrane Proteins
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NOTCH2 protein, human
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NTN1 protein, human
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Nerve Growth Factors
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Receptor, Notch2
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Recombinant Proteins
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Serrate-Jagged Proteins
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Tumor Suppressor Proteins
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Netrin-1