| Zur Übersicht | |||
|
|||
| Art des Jobs | Vollzeit | |
| Eingetragen am | 06.05.2024 | |
| Einsatzort | Heidelberg | |
| Jobbeschreibung | Job description: Enzymology of Protein Kinase Regulation by RNA Helicases Wnt signaling is a key process in cell differentiation and oncogenesis. Casein kinase 1 (CK1) regulates Wnt signaling pathway at multiple levels. The lab of Prof. Dr. Christof Niehrs has identified the DEAD-box RNA helicase DDX3 as effector of the Wnt-?-catenin network, where it acts as an activator of CK1 (Cruciat, 2013; Fatti, 2023). Both DDX3 and CK1 are oncogenes and hence their investigation is of relevance for the development of novel cancer therapeutics. Our data indicate that DDX3 allosterically activates CK1 (Fatti, 2023). You will follow-up on the kinetic mechanism of this new regulatory paradigm between kinases and helicases by conducting recombinant protein expression, enzyme kinetics, and biophysical measurements, including stopped flow spectroscopy, to provide a mechanistic understanding. References: Cruciat et al. (2013). RNA helicase DDX3 is a regulatory subunit of casein kinase 1 in Wnt-?-catenin signaling. Science 339, 1436-1441. Fatti E et al. (2023) DEAD-box RNA Helicases Act as Nucleotide Exchange Factors for Casein Kinase 2. Science Signalling 16, eabp8923 Engineering Novel ROTACs for Oncoprotein Targeting Proteolysis-targeting chimeras (PROTACs) for targeted protein degradation are an emerging technology for therapeutic intervention, but options to target cell surface proteins and receptors remain limited. We recently developed ROTACs, bispecific Wnt and BMP signaling disabled R-spondin (RSPO) chimeras, which leverage the specificity of these stem cell growth factors for ZNRF3/RNF43 E3 transmembrane ligases, to target degradation of transmembrane proteins (Sun, 2023). We are now developing new ROTACs targeting a variety of transmembrane proteins towards development of novel cancer therapies. The project involves engineering new ROTAC constructs, expression of recombinant proteins, and testing in various cell-based assays for target binding and degradation efficacy. References: Sun R, Lee H, Niehrs C (2023) ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation. Cell Chem Biol doi: 10.1016/j.chembiol.2023.05.010 Cilia as Wnt Signaling Organelles in Xenopus Embryogenesis Cilia and Wnt signaling have a complex relationship, wherein Wnt regulates cilia and, conversely, cilia may affect Wnt signaling. Recently, we showed that Wnt receptors are present in flagella, primary cilia, and multicilia, where they transmit an intraciliary signal that is independent of ?-catenin (Koch, 2015; Zhang, 2023; Seidl, 2023). Intraciliary Wnt signaling promotes ciliogenesis, affecting male fertility, adipogenesis, and mucociliary clearance. Wnt also stimulates the beating of Xenopus tadpole motile cilia, highlighting that these nanomotors too, are chemosensory. Collectively, these findings support that cilia are Wnt signaling organelles, with implications for ciliopathies and cancer. In this project, you will investigate the role of Wnt signaling in the mucociliary epidermis of Xenopus embryos and tadpoles (Seidl, 2023). This epidermis is a widely used model for cilia akin to human airway epithelia. It harbors multiciliary bundles beating in a polarized direction to generate fluid flow from head to tail of the embryo that removes pathogens and aids oxygenation. You will study the role and mechanism of action whereby Wnt stimulates ciliary beating. You will apply Xenopus embryo micromanipulation and other developmental biology techniques, along with transcriptome and proteome analysis as well as techniques specific to cilia cell biology. References: Koch et al. (2015) Post-transcriptional Wnt Signaling Governs Epididymal Sperm Maturation. Cell 163(5):1225-1236 Zhang et al. (2023) Primary cilia are WNT-transducing organelles whose biogenesis is controlled by a WNT-PP1 axis. Dev Cell 58(2):139-154. Seidl et al. (2023) Mucociliary Wnt signalling promotes cilia biogenesis and beating. Nat. Commun. 6;14:1259 |
| Qualifikationen | Requirements:
Applicants should hold a master's degree in life sciences with a background in cell or molecular biology, biochemistry, or developmental biology depending on the project. You should be highly self-motivated and be able to pursue research projects independently as well as in collaborations. An excellent written and oral command of English is essential. Please add a single PDF file including CV, certificates (Germans: copies of Abitur- & Masters degree), a cover letter stating research and career interests, expected availability date, a list of publications and have two letters of reference. Please also specify in your cover letter which project is the most interesting for you. Incomplete applications will not be considered or acknowledged. |
| Firma |
Deutsches Krebsforschungszentrum 69120 Heidelberg |
| Link zu weiteren Informationen | |
| Zur Übersicht | |