Signal transduction in receptor-mediated apoptosis and cell survival

Apoptosis is an active form of cellular self-destruction that enables an organism to delete unwanted cells, thereby playing an essential role during development and in tissue homeostasis. Apoptosis involves characteristic changes in cell morphology, including cell shrinkage, membrane blebbing, and fragmentation of the cell nucleus. Apoptotic cells are rapidly phagocytozed by neighbouring cells or macrophages and, thus, do not cause inflammation in their surrounding tissue.

CD95-mediated ERK signaling

We previously observed that death receptors can induce ERK phosphorylation and protect the cells from apoptosis. We are currently establishing the molecular mechanisms underlying the ability of CD95 to activate ERK, and how death-effector domain containing proteins may contribute to this signaling pathway.

Regulation of c-FLIP by post-translational modification

The activity of c-FLIP, like most cellular proteins, can be regulated at the protein level by post-translational modifications. We previously demonstrated that stability of the short isoforms is regulated by classical PKC-mediated phosphorylation on a serine in the prodomain of the protein.

Our current findings reiterate the localization of c-FLIPL predominantly in nucleus and importantly reveal for the first time a single phosphorylation-based switch, which promptly induces an isoform-specific shift in the subcellular distribution of c-FLIP in response to signals originating from activated death receptors.

Ongoing research in this area, seeks to address the specificity of c-FLIP phosphorylation upon various death ligand treatments; as well as to investigate the role of phosphorylation c-FLIP in the regulation of non-apoptotic pathways such as NF-?B activation.

c-FLIP regulation of cell population size

Our recent findings show that the c-FLIP phosphorylation on certain amino acid residues is increased during mitosis, and that the phosphorylated pool of c-FLIP proteins is to be found accumulated at the centrosome throughout the cell cycle. In addition, we observe that overexpression of wild type c-FLIPL potently increases the cell count, whereas overexpression of the phospho-deficient mutant c-FLIPL does not. An increase in spontaneous cell death among cells overexpressing the phospho-deficient c-FLIPL was observed compared to cells overexpressing wild type c-FLIPL.

c-FLIP cytoplasmic filaments

Preliminary findings from our lab suggest a propensity for c-FLIP to form filamentous-like structures in the cytoplasm of certain cell lines. We are currently investigating the mechanistic and functional significance of this observation.

Modeling dead and alive: in silico model of cell fate

Cross disciplinary research between biology and in silico modeling is a rapidly expanding field of science to analyze the complex system biology. We use a systems-oriented approach to build experimentally validated models to study cell survival and death signaling pathways.
Our current modelling task involved the construction of a single cell model to investigate and analyze the dynamics of isoform-specific c-FLIP phosphorylation receptor-mediated cell death signaling. Continuous research involves accounting for phenotypic variability among cell populations and how this heterogeneity affects the phosphorylation-mediated responses in regulating cell fate decisions.

Plant-derived compounds and their role in apoptosis

Plant lignans sensitize prostate cancer cells to TRAIL-mediated apoptosis. Our group has shown that lignans have the ability to sensitize TRAIL-resistant prostate cancer cells for TRAIL-mediated apoptosis. Our current aims are to characterize the key structural features for their function and to further define their mechanism of action. This and other similar projects aiming at sensitization of cells to apoptotic signaling are going on as technology transfer initiatives (see Technology Transfer section for more information on this topic).

Responsible Team Members

  • Alia Joko
  • Erik Niemelä
  • Preethy Paul