Erhart, Dominik. Control of cellular signals in time and space. 2012, PhD Thesis, University of Basel, Faculty of Science.
Restricted to Repository staff only until 01 December 2013.
Official URL: http://edoc.unibas.ch/diss/DissB_9781
Most cellular processes involve dynamic interactions of signaling proteins. Chemical inducers of protein dimerization have been used to monitor and control these interactions in a spatial and temporal manner. These so called “dimerizers” are cell-permeable, small organic molecules that bind to specific tag protein domains. The most widely used systems is based on rapamycin as a dimerizer, which induces a tight binding between FKBP12 and the so-called FRB domain of mammalian target of rapamycin (mTOR). Although elegant and fast, the rapamycin-based system cannot be used to study proteins involved in growth and metabolism due to mTOR inhibition. In this PhD thesis we developed of a novel heterodimerization system based on protein tags devoid of endogenous signaling counterparts. Extensive structure modifications of these dimerizers in a pharmacochemical manner afforded highly cell permeable molecules that can dimerize proteins intracellularly. With the control of these molecules we now are not only able to dimerize any protein of interest, but can also target them to any selected cellular compartment. Utilizing this ability to target proteins to specific cellular domains, we could demonstrate that the dimerizer induced translocation of effector proteins to the plasma membrane led to a subsequent activation of downstream targets. This was shown by the translocation of the iSH2 domain of the regulatory subunit p85 of PI3K to the plasma membrane and the activation of the PI3K/PKB/mTOR pathway. In contrast to receptor ligand induced multiple pathway activation, our system has the power of a molecular button, activating single signaling cascades without affecting others. The presented small molecule-induced heterodimerization system is suitable to selectively control signaling pathways in time and space, without affecting endogenous signaling systems.
|Advisors:||Wymann, Matthias Paul|
|Committee Members:||Johnsson, Kai|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Institute of Biochemistry and Genetics > Cancer- and Immunobiology (Wymann)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||156 S.|
|Last Modified:||27 Mar 2012 16:18|
|Deposited On:||27 Mar 2012 16:18|
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