- Project I
- Project II
- Project III
RAF-MAPK signaling
Our major interests are in understanding how regulatory signals are transmitted from growth receptors to intracellular targets. RAS proteins are small GTPases, which control various signalling cascades modulating normal cell growth, proliferation, migration, differentiation, and oncogenic transformation. It is now estimated that ~20% of all human tumors have activating mutations in one of the RAS genes. RAS proteins upon activation bind to a number of effector proteins to trigger various signaling pathways. RAF kinases are major RAS effector proteins, which directly binds to RAS and initiates the highly conserved RAF-MEK-ERK cascade. One of our major aims is to understand how RAF kinase signaling is orchestrated in normal and tumor cells (Rajalingam et.al NCB 2005, Dogan et.al NCB 2008). We have identified a role for a highly conserved protein called prohibitin in the activation of C-RAF and cell migration in vivo (Rajalingam et.al NCB 2005, Fischer et.al JBC 2008). We would like to further characterize the role of prohibitins and other RAF binding proteins in modulating various cellular processes.
Figure 1. Silencing of prohibitin (PHB) reduces spreading and increases intercellular adhesion in HeLa cells (Image provided by Dr.Volker Brinkmann, MPIIB, Berlin). Proposed model demonstrating a role for PHB in the activation of C-RAF in vivo (adapted from Fischer et.al JBC 284(5):3183-94)
Inhibitors of Apoptosis
Inhibitors of Apoptosis (IAPs) are the only known endogenous inhibitors of caspases. During apoptosis, Smac/DIABLO and Omi/HtrA2 are released from the mitochondria to displace IAPs so that the caspases can be activated. We have uncovered that IAPs are constitutively organized into heteromeric protein complexes (IAP-IAP complexes/IAPosome) to modulate the stability of each other and the survival of the cell (PLoS Pathog. 2(10):e114). In a recent breakthrough, we have identified a novel role for IAPs in modulating the stability of C-RAF kinase and cell motility (Dogan et. al. NCB 2008). The major objective of this project is to elucidate the components of IAP-IAP/IAP-RAF signaling complexes, their dynamics and role in various cellular processes.
Figure 2. Silencing of XIAP leads to stabilization of C-RAF and enhanced cell migration in human cells. XIAP binds to C-RAF and promotes the degradation of C-RAF via Hsp90-mediated protein quality control system (Model as proposed in NCB 2008).
Apoptosis signaling
In addition, we employ proteomics-mass spectrometry and RNAi approaches to identify novel cell death regulators. We are interested Mitochondrial Outer Membrane Permeabilisation (MOMP), one of the major events that occur during apoptosis. MOMP is accomplished by the activation of proapoptotic Bcl-2 family members Bax and Bak by mechanism(s) which are not well understood so far. We exploit various infection and toxin models to understand this process and to further elucidate how cell death signaling is orchestrated in human cells.
Funding
The research group is currently funded by the Emmy Noether Programme of the German research Foundation (2007-2012) as well as by the institutional grants from the Institute for Biochemisty II, Goethe University Medical School.