Project Description:
The secretory pathway is essential for many processes of all eukaryotic cells where it plays crucial roles in the synthesis, transport and turnover of many functional components of cells, ranging from protein involved in cell signaling to organelle functions. Consequently, the processes of the secretory pathway are subject to extensive quality control regulations, monitoring the folding, assembly, covalent modification, processing and transport of its various constituents and cargo molecules. This involves a complex network of feedback control mechanisms ensuring that each organelle of the secretory pathways retains its vital functions under conditions of stress. The down side of this robust system is that it permits not only stressed cells, but also malignant cells such as cancer cells to coop with challenges that have the potential to severely impact the homeostasis of the secretory pathway and the secreted proteome (‘secretome’). This can lead to high levels of mis-targeted and mis-folded proteins, which have to be removed by various degradation pathways. It is now well established that for example several types of cancer cells are sensitive to disturbances in the quality control and ‘waste disposal’ systems of the secretory pathway, which therefore constitute prime targets for therapies. In this project we aim at developing new biochemical methods to characterize the components of the secretome that are recognized by protein quality control systems as a function of cancer types or disease states. This will eventually enable us to better tailor therapies and to interfere with such disease. The project focuses on proteomics and cell biological analysis of biological and medical samples and will employ methods from cell biology, mass spectroscopy and bioinformatics.
References:
Anderson, D.J., R. Le Moigne, S. Djakovic, B. Kumar, J. Rice, S. Wong, J. Wang, B. Yao, E. Valle, S. Kiss von Soly, A. Madriaga, F. Soriano, M.-K. Menon, Z.Y. Wu, M. Kampmann, Y. Chen, J.S. Weissman, B.T. Aftab, F.M. Yakes, L. Shawver, H.-J. Zhou, D. Wustrow, and M. Rolfe. 2015. Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis. Cancer Cell. 28:653–665. doi:10.1016/j.ccell.2015.10.002.
Dona, E., J.D. Barry, G. Valentin, C. Quirin, A. Khmelinskii, A. Kunze, S. Durdu, L.R. Newton, A. Fernandez-Minan, W. Huber, M. Knop, and D. Gilmour. 2013. Directional tissue migration through a self-generated chemokine gradient. Nature. 503:285–289. doi:10.1038/nature12635.
Heinrich, S., E.-M. Geissen, J. Kamenz, S. Trautmann, C. Widmer, P. Drewe, M. Knop, N. Radde, J. Hasenauer, and S. Hauf. 2013. Determinants of robustness in spindle assembly checkpoint signalling. Nat. Cell Biol. 15:1328–1339. doi:10.1038/ncb2864.
Khmelinskii, A., E. Blaszczak, M. Pantazopoulou, B. Fischer, D.J. Omnus, G. Le Dez, A. Brossard, A. Gunnarsson, J.D. Barry, M. Meurer, D. Kirrmaier, C. Boone, W. Huber, G. Rabut, P.O. Ljungdahl, and M. Knop. 2014. Protein quality control at the inner nuclear membrane. Nature. 516:410–413. doi:10.1038/nature14096.
Khmelinskii, A., P.J. Keller, A. Bartosik, M. Meurer, J.D. Barry, B.R. Mardin, A. Kaufmann, S. Trautmann, M. Wachsmuth, G. Pereira, W. Huber, E. Schiebel, and M. Knop. 2012. Tandem fluorescent protein timers for in vivo analysis of protein dynamics. Nat. Biotechnol. 30:708–714. doi:10.1038/nbt.2281.
Methods that will be used:
Yeast genetics, cell culture, mass spectroscopy, diverse range of cell biology methods (microscopy etc.)
Profile of candidate’s qualification:
Molecular biology, cell biology, biochemistry, solid knowledge in basic statistics, good computing skills beyond MS Word and Excel (e.g. R)
Keywords:
Protein quality control in the endoplasmic reticulum in healthy and sick cells
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