Gamma-secretase-independent role for cadherin-11 in neurotrophin receptor p75 (p75^NTR) mediated glioblastoma cell migration

The p75 neurotrophin receptor (p75^NTR) undergoes γ-secretase-mediated regulated intramembrane proteolysis and is involved in glioblastoma cell migration and invasion. Consistent with previous reports, in this study we show that p75NTR increases U87-MG glioblastoma cell migration, which is reversed by inhibition of γ-secretase activity. However, we show that expression or stabilization of the γ-secretase-generated p75^NTR intracellular domain (ICD) is not sufficient to induce U87-MG glioblastoma cell migration, and that exogenous expression of p75^NTR ICD inhibits p75^NTR-mediated glioblastoma cell (U87-MG and U373-MG) migration. To identify pathways and to determine how p75^NTR mediates glioblastoma migration we utilized a microarray approach to assess differential gene expression profiles between parental U87-MG and cells stably expressing wild-type p75^NTR, a γ-secretase cleavage-resistant chimeric p75^NTR mutant (p75FasTM) and the γ-secretase-generated p75^NTR-ICD, which mimics constitutively cleaved p75^NTR receptor. In our microarray data analysis we identified a subset of genes that were constitutively up-regulated in wild-type p75^NTR cells, which were also repressed in p75^NTR ICD expressing cells. Furthermore, our data revealed among the many differentially expressed genes, cadherin-11 (Cdh-11), matrix metalloproteinase 12 and relaxin/insulin-like family peptide receptor 2 as constitutively up-regulated in wild-type p75^NTR cells, independent of γ-secretase activity. Consistent with a role in glioblastoma migration, we found that U87-p75^NTR cells express higher levels of Cdh-11 protein and that siRNA-mediated knockdown of Cdh-11 resulted in a significant decrease in p75^NTR-mediated glioblastoma cell migration. Therefore, we hypothesize that p75^NTR can impact U87-MG glioblastoma cell migration in a γ-secretase-independent manner through modulation of specific genes, including Cdh-11, and that both γ-secretase-independent and -dependent mechanisms are involved in p75^NTR-mediated U87-MG glioblastoma cell migration.