Thesis supervisor: György Vámosi
Location of studies (in Hungarian): Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen Abbreviation of location of studies: DEBSI
Description of the research topic:
Membrane receptors bind ligands arriving from the external environment of the cell or from the cell itself to which the cell gives an adequate response. Depending on whether the ligand is produced by a distant or nearby tissue, possibly by the cell itself, we can speak of an endocrine, paracrine, or autocrine signaling mechanism. Our group recently discovered a novel intracrine mechanism for interleukin-2, the receptor of which is located in the membrane of T cells. In the newly described mechanism, signaling in a T cell that also produces IL-2 receptor subunits and IL-2 ligand may occur before the receptor and ligand reach the cell membrane. Using FRET, we have shown that the three subunits of IL-2R are already partially assembled into a heterotrimer in the endoplasmic reticulum and Golgi, and when the T cell also produces IL-2, IL-2R is able to bind and signal in the Golgi lumen and induce cell division. Overexpression of IL-2R in many cases causes uncontrolled T cell proliferation, e.g. in adult T-cell leukemia (ATL). Anti-IL-2R (daclizumab) inhibitory therapy is used to treat ATL (or to prevent organ rejection or autoimmune disease) but is ineffective in the acute form of ATL. This is presumably due to the intracrine mechanism we have described. There are several other receptors that also act by an autocrine mechanism against which inhibitory antibody therapy exists. The efficacy of such therapies may be hampered if the cell is able to transmit the signal by the intracrine mechanism mentioned above before the receptor reaches the cell membrane. Therefore, we aim to investigate the presence of the above intracrine mechanism in the case of further receptors. This may define a new paradigm in signal transduction, and direct therapies toward intracellular target molecules, e.g. ic. kinases. We first plan to examine the epidermal growth factor receptor. EGFR (ErbB1) is involved in the pathogenesis of breast cancer, non-small cell lung cancer, and certain tumors of the colon, head and neck, kidneys, pancreas, and ovaries. The receptor tyrosine kinase acts as a dimer. Upon ligand binding, receptors cross-phosphorylate each other, initiating MAPK, JNK, PI3K pathways and inducing cell division. We wish to study receptor oligomrization, ligand binding and signaling in the Golgi apparatus. If the experiments are successful, the studies will be extended to heterodimers of related receptors (ErbB2, ErbB3) involved in breast cancer.
Required language skills: English intermediate level Number of students who can be accepted: 2
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