Prof. Dr. Gerald Radziwill
The RAF/MEK/ERK and the PI3K/AKT pathways regulate biological processes including cell proliferation, differentiation and survival. Dysregulation of these pathways promotes tumorigenesis. Recently, we published the first light-controllable protein kinase, optoRAF, based on the light-dependent dimerisation of the photoreceptor cryptochrome 2 from Arabidopsis thaliana fused to RAF.
OptoRAF enables the activation of RAF independently of growth factors in a space and time resolved manner. We apply optoRAF to further study RAF signalling and to characterize clinical inhibitors used in tumour therapy.
Scaffold proteins comprise multiple protein-protein interaction domains and function as hubs to coordinate signalling networks. We identified CNK1 as scaffold protein that interacts with RAF and AKT and thereby regulates normal and oncogenic signalling. Growth factors induce oligomerisation and activation of CNK1. We engineered OptoCNK1 that allows fine-tuning of oligomerisation stimulating either ERK or AKT signalling. We now study the role of CNK1 as an essential mediator of cell fate decisions in a cell type and cell stage-dependent manner. In addition, we designed further optogenetic tools including optoAKT. All these optogenetic tools will facilitate the study on the dynamics of signalling processes that controls cell behaviour.
10 selected publications:
- Optogenetics – Bringing light into the darkness of mammalian signal transduction.
Mühlhäuser WW, Fischer A, Weber W, Radziwill G. (2017)
Biochim Biophys Acta - Mol Cell Res 1864, 280-292.
- AKT-dependent phosphorylation of the SAM domain induces oligomerization and activation of the scaffold protein CNK1.
Fischer A, Weber W, Warscheid B, Radziwill G. (2017)
Biochim Biophys Acta - Mol Cell Res 1864, 89-100.
- Optogenetic clustering of CNK1 reveals mechanistic insights in RAF and AKT signaling controlling cell fate decisions.
Fischer A, Warscheid B, Weber W, Radziwill G. (2016)
Scientific Reports 6:38155.
- Optogenetically controlled RAF to characterize BRAF and CRAF protein kinase inhibitors.
Chatelle CV, Hövermann D, Müller A, Wagner HJ, Weber W, Radziwill G. (2016)
Scientific Reports 6:23713.
- Differential tyrosine phosphorylation controls the function of CNK1 as a molecular switch in signal transduction.
Fischer A, Brummer T, Warscheid B, Radziwill G. (2015)
Biochim Biophys Acta - Mol Cell Res 1853, 2847-2855.
- Optogenetic control of protein kinase activity in mammalian cells.
Wend,S, Wagner HJ, MüllerK, Zurbriggen MD, Weber W, Radziwill G. (2014)
ACS Synth Biol 3, 280-285.
- Modularized CRISPR/dCas9 effector toolkit for target-specific gene regulation.
Agne M, Blank I, Emhardt AJ, Gäbelein CG, Gawlas F, Gillich N, Gonschorek P, Juretschke TJ, Krämer SD, Louis N, Müller A, Rudorf A, Schäfer LM, Scheidmann MC, Schmunk LJ, Schwenk PM, Stammnitz MR, Warmer PM, Weber W, Fischer A, Kaufmann B, Wagner HJ, Radziwill G. (2014)
ACS Synth Biol 3, 986-989.
- CNK1 is a novel Akt interaction partner that promotes cell proliferation through the Akt/FoxO signalling axis.
Fritz RD, Varga Z, Radziwill G. (2010)
Oncogene 29, 3575-3582.
- CNK1 promotes invasion of cancer cells through NF-kappaB-dependent signalling.
Fritz RD, Radziwill G. (2010)
Mol Cancer Res 8, 395-406.
- The scaffold protein CNK connects Raf-1 and Src signalling.
Ziogas A, Moelling K, Radziwill G. (2005)
J Biol Chem 280, 24205-24211.