Yuhua, Wang. Identifying the role of Mer receptor tyrosine kinase in glioblastoma multiforme. 2012, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10047
MerTK is a member of the TAM receptor tyrosine kinase family, which is characterized by a conserved sequence within the kinase domain and a combination of two N-terminal immunoglobulin (Ig)-like domains and two fibronectin type III (FNIII) repeats in their extracellular regions. Although protein S and Gas6 are the putative ligands of TAM kinases, several other proteins have been proposed recently to activate TAM receptors, suggesting the existence of additional mechanisms for TAM activation. Full activation of MerTK requires the autophosphorylation of tyrosines 749, 753 and 754 within the kinase domain and co-immunoprecipitation experiments indicate that several signaling molecules associate with phosphorylated tyrosine 872 of MerTK in the catalytic domain. MerTK appears to be required for ingestion of apoptotic cells by phagocytes such as monocytes/macrophages, and also by retinal pigment epithelial cells and dendritic cells. Overexpression of MerTK has been reported in many cancer types, including breast and prostate cancer, lymphoma and leukemia. Recently, MerTK was found to be upregulated in the mesenchymal subtype of primary GBMs and depletion of MerTK increases astrocytoma cell chemosensitivity. Nevertheless, the mechanisms of MerTK activation and its activity in brain tumor progression remain unclear.
In this study, MerTK was found to be overexpressed in GBM and GBM-derived spheres compared with non-neoplastic brain tissue and normal human astrocytes, and this is mitigated upon differentiation. Low expression of MerTK was also observed in conventional immortalized GBM cell lines. Co-staining MerTK with the astrocytic marker GFAP (glial fibrillary acidic protein) indicates that MerTK is expressed in the GFAP+ cell lineage in GBM samples. MerTK maintains the amoeboid rounded morphology of GBM cells under stem cell culture conditions and MerTK is upregulated in U373 GBM cells cultured in serum-free NBM (neural basal medium). In vivo studies have shown that glioma cells migrate in an amoeboid mode due to structural constraints in the neural ECM. Immunofluorescence staining of U373 cells shows intensive blebbing of the cell membrane, which is a typical morphological marker of amoeboidly migrating cells. Knockdown of MerTK not only disrupts rounded cell morphology but also decreases cell infiltrative capacity and increases cell sensitivity to etoposide-induced apoptosis. It was further shown that MerTK autophosphorylation is essential for its anti-apoptotic and pro-invasive activities. Depletion of MerTK attenuates the expression and phosphorylation of MLC2. The results obtained have uncovered a novel activity of MerTK in GBM progression and these findings promote MerTK as a potential therapeutic target in the treatment of GBM, in combination with radio/chemotherapy.
|Advisors:||Hemmings, Brian A.|
|Committee Members:||Ballmer-Hofer, Kurt|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum|
|Bibsysno:||Link to catalogue|
|Number of Pages:||124 S.|
|Last Modified:||30 Jun 2016 10:50|
|Deposited On:||17 Oct 2012 14:45|
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