Position: Postdoc in Phase Separation & RNA Helicases in Wnt Signaling

Department: Molecular Embryology

Code number: 2024-0140

The German Cancer Research Center is the largest biomedical research institution in Germany. With more than 3,000 employees, we operate an extensive scientific program in the field of cancer research.

The Division of Molecular Embryology (headed by Prof. Dr. Christof Niehrs) is looking for a postdoc for one of the following three projects to start as soon as possible.

 

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-β-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-β-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 β-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

 

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.  

We offer:

  • Interesting, versatile workplace
  • Excellent framework conditions: state-of-the-art equipment and opportunity for international networking at the highest level
  • Remuneration according to TV-L incl. occupational pension plan for the public service and capital-forming payments
  • 30 days of vacation per year
  • Flexible working hours
  • Possibility of mobile work and part-time work
  • Family-friendly working environment, including parent-child room, counseling services, e.g. on Elder Care
  • Sustainable travel to work: subsidized Germany job ticket
  • Develop your full potential: access to the DKFZ International Postdoc Program and DKFZ Career Service with targeted offers for your personal development to further develop your talents
  • Our Corporate Health Management Program offers a holistic approach to your well-being

Important notice:

The DKFZ is subject to the regulations of the Infection Protection Act (IfSG). As a consequence, only persons who present proof of immunity against measles may work at the DKFZ.

Earliest possible start date: as soon as possible

Duration: The position is initially limited to 2 years with the possibility of prolongation. ‚Äč

Application deadline: 14.06.2024

Contact:

Prof. Dr. Christof Niehrs
Phone +49 (0)6221-42 4690

Please note that we do not accept applications submitted via email.

The DKFZ is committed to increase the proportion of women in all areas and positions in which women are underrepresented. Qualified female applicants are therefore particularly encouraged to apply.

Among candidates of equal aptitude and qualifications, a person with disabilities will be given preference.

To apply for a position please use our online application portal (https://www.dkfz.de/en/stellenangebote/index.php).

We ask for your understanding that we cannot return application documents that are sent to us by post (Deutsches Krebsforschungszentrum, Personalabteilung, Im Neuenheimer Feld 280, 69120 Heidelberg) and that we do not accept applications submitted via email. We apologize for any inconvenience this may cause.