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Mannose phosphate isomerase regulates fibroblast growth factor receptor family signaling and glioma radiosensitivity.
- Source :
-
PloS one [PLoS One] 2014 Oct 14; Vol. 9 (10), pp. e110345. Date of Electronic Publication: 2014 Oct 14 (Print Publication: 2014). - Publication Year :
- 2014
-
Abstract
- Asparagine-linked glycosylation is an endoplasmic reticulum co- and post-translational modification that enables the transit and function of receptor tyrosine kinase (RTK) glycoproteins. To gain insight into the regulatory role of glycosylation enzymes on RTK function, we investigated shRNA and siRNA knockdown of mannose phosphate isomerase (MPI), an enzyme required for mature glycan precursor biosynthesis. Loss of MPI activity reduced phosphorylation of FGFR family receptors in U-251 and SKMG-3 malignant glioma cell lines and also resulted in significant decreases in FRS2, Akt, and MAPK signaling. However, MPI knockdown did not affect ligand-induced activation or signaling of EGFR or MET RTKs, suggesting that FGFRs are more susceptible to MPI inhibition. The reductions in FGFR signaling were not caused by loss of FGF ligands or receptors, but instead were caused by interference with receptor dimerization. Investigations into the cellular consequences of MPI knockdown showed that cellular programs driven by FGFR signaling, and integral to the clinical progression of malignant glioma, were impaired. In addition to a blockade of cellular migration, MPI knockdown also significantly reduced glioma cell clonogenic survival following ionizing radiation. Therefore our results suggest that targeted inhibition of enzymes required for cell surface receptor glycosylation can be manipulated to produce discrete and limited consequences for critical client glycoproteins expressed by tumor cells. Furthermore, this work identifies MPI as a potential enzymatic target for disrupting cell surface receptor-dependent survival signaling and as a novel approach for therapeutic radiosensitization.
- Subjects :
- Cell Line, Tumor
Cell Membrane metabolism
Cell Movement genetics
Cell Proliferation
Gene Knockdown Techniques
Glioma genetics
Glioma radiotherapy
Humans
Mannose-6-Phosphate Isomerase genetics
Protein Multimerization
Protein Transport
RNA, Small Interfering
Receptor Protein-Tyrosine Kinases metabolism
Receptor, Fibroblast Growth Factor, Type 2 chemistry
Receptor, Fibroblast Growth Factor, Type 2 genetics
Receptor, Fibroblast Growth Factor, Type 2 metabolism
Receptors, Fibroblast Growth Factor chemistry
Receptors, Fibroblast Growth Factor genetics
Glioma metabolism
Mannose-6-Phosphate Isomerase metabolism
Radiation Tolerance genetics
Receptors, Fibroblast Growth Factor metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 9
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25314669
- Full Text :
- https://doi.org/10.1371/journal.pone.0110345