p75 Neurotrophin Receptor Cleavage by {alpha}- and {gamma}-Secretases is required for Neurotrophin mediated proliferation of Brain Tumor Initiating Cells. [Molecular Bases of Disease]

February 11th, 2014 by Forsyth, P. A., Krishna, N., Lawn, S., Valadez, J. G., Qu, X., Fenstermacher, D. A., Fournier, M., Potthast, L., Chinnaiyan, P., Gibney, G. T., Zeinieh, M., Barker, P. A., Carter, B. D., Cooper, M. K., Kenchappa, R. S.

Malignant gliomas are highly invasive, proliferative, and resistant to treatment. Previously, we have shown that p75NTR is a novel mediator of invasion of human glioma cells. However, p75NTR role in glioma proliferation is unknown. Here we used Brain Tumor Initiating Cells (BTICs), and show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB and TrkC), their ligands (NGF, BDNF and NT3), and secrete NGF. Down regulation of p75NTR significantly decreased BTICs proliferation. Conversely, exogenouous NGF, stimulated BTIC proliferation through α- and γ-secretase mediated p75NTR cleavage and release of its intracellular domain. In contrast, overexpression of the p75NTR-ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF stimulated BTIC proliferation and p75NTR cleavage; implicate the Trks role in p75NTR signaling. Further, blocking p75NTR cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR mediated proliferation. We also found that p75NTR, α-secretases and the 4 subunits of the γ-secretase enzyme were elevated in GBM patients. Importantly, the ICD of p75NTR was commonly found in malignant glioma patient specimens suggesting that the receptor is activated and cleaved in patient tumors. These results suggest that these might be clinically relevant and p75NTR proteolysis is required for BTIC proliferation and is a novel potential clinical target.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on p75 Neurotrophin Receptor Cleavage by {alpha}- and {gamma}-Secretases is required for Neurotrophin mediated proliferation of Brain Tumor Initiating Cells. [Molecular Bases of Disease]