Research areas
Key words: Endoplasmic reticulum, Proteostasis, Golgi apparatus, COPII, Kinases, Rho-GTPases, Cell migration, Breast cancer, Multiple myeloma, Protein Aggregation, Mitosis, Ubiquitin, F-box proteins, Pseudophosphatase, Pseudoenzyme, Ubiquitin ligases, Aneuploidy, Cancer metastasis, Cell cycle, Cell adhesion
- Regulation of Endoplasmic reticulum (ER) proteostasis
A third of the proteome is composed of secretory proteins. The endoplasmic reticulum (ER) is the first station along the secretory journey of a protein, thus making the ER is a major hub for protein homeostasis (proteostasis). Our research focuses on the mechanisms that connect cell growth and quiescence with the regulation of ER morphology and function. Furthermore, we are investigating lectin-type cargo receptors such as ERGIC-53 (LMAN1), VIP36 (LMAN2) and VIPL (LMAN2L), trying to identify novel cargos that are uses these receptors for the exit from the ER. Finally, we aim to understand the role of ER-export in diseases such as multiple myeloma. This type of cancer is characterized by excessive secretory activity. Our aim is to uncover which components of the ER-export machinery are most critical to myeloma cells and thereby identify novel therapeutic targets.
Utku Horzum, Yannick Frey, Veronika Reiterer, Laura Sammarco, Margot Haun, Gabriele Stöckl, Renata Hajdu
- Mechanobiology of the ER
Our cells are constantly exposed to a variety of mechanical forces such as tensile stress, hydrostatic pressure, compression, or confinement. Mechanosensors sense these forces and convert them into biochemical signals that regulate cellular functions (mechanotransduction). The main focus of the community centered on the role of the plasma membrane and the nucleus in mechanosensing and mechanotransduction. Our previous work (Phuyal et al, EMBOJ, 2022) showed that mechanical forces elicit signaling pathways that regulate export from the ER. Our current work tests the hypothesis that the ER is capable of sensing mechanical forces and elicits mechanotransduction signaling that emanates from the ER. The ER is the largest cellular organelle that spans that almost the entire cellular area. Therefore, it is conceivable that most mechanical forces will also affect the structure and function of the ER. We are currently trying to identify and ER-based mechanosensor as well as characterize lipidomic changes of the ER under mechanical stress.
Michaela Mayr, Alexander Plesche, Luiz Garcia
- Tumor microenvironment and cancer cell adhesion
Changes in the microenvironment are critical in cancer progression. Locally activated fibroblasts, known as cancer-associated fibroblasts (CAFs), play a key role in altering the extracellular matrix’s protein composition, rearranging its structure, and influencing various physical characteristics of the tissue. We have recently shown that CAFs decorate their migration paths with tracks, specialized extracellular vesicles that enhance cancer cell adhesion through a specific type of adhesive structures called endocytosis-related adhesions. Cancer cells not only adhere to tracks, but also internalize them, along with their content. Our goal is to describe the changes induced in cancer cells upon internalization of CAF-tracks.
All the modifications occurring in the tumor microenvironment generate a challenging environment for disseminating cancer cells, which need to adapt to successfully metastasize. Establishing adhesions to the surrounding environment is vital for these cells to evade cell death. Hence, metastatic cells must exhibit significant plasticity in their adhesive capacities. Aim of our group is to study how metastatic cancer cells switch between different types of adhesions in response to the evolving characteristics of the tumor microenvironment. Specifically, we seek to characterize the recently discovered endocytosis-related adhesions, whose role and significance in comparison to the conventional focal adhesions are yet to be fully understood.
Francesco Baschieri, Francois Tyckaert, Maria Reichhold, Pere Patrón González, Natalia Regina Melo Santos
- Pseudophosphatases as regulators of F-box Proteins
All major enzyme families contain members with mutations in conserved domains that predict alteration their catalytic activity. These members are referred to as pseudoenzymes. In the human phosphatome, pseudophosphatases make up 14% of all phosphatases. We are investigating STYX, an archetype pseudophosphatase. Our working hypothesis is that the loss of enzymatic activity allows pseudophosphatases like STYX to adopt new cellular functions that go beyond crosstalk with kinases. In fact, we found that STYX regulates several F-box proteins (FBPs). FBPs are part of ubiquitin-ligase complexes and their function is to bind the substrates destined for ubiquitylation. We are characterizing the role of STYX in the regulation of several F-box proteins such as FBXW7, FBXO31, FBXL12 and FBXW4.
Veronika Reiterer
- Cell Division and Cell Cycle Control
The fidelity of chromosome segregation during cell division is essential for maintaining the genetic information of proliferating cells. We are interested in the mechanistic aspects of mitosis and try to understand how microtubule-based motor proteins (dynein, kinesin) and their associated proteins (e.g. the kinetochore protein Spindly) contribute to chromosome congression and how errors in these processes cause activation of the spindle assembly checkpoint. This checkpoint controls the activity of the APC/C, a ubiquitin ligase that targets a small number of proteins for proteasome-dependent degradation. The APC/C is, however, not only essential for mitosis but also plays an important role in G1-phase. We are interested in defining novel functions of the APC/C outside when it is mainly activated by CDH1/Fzr1. Entry and exit from mitosis is governed by a cyclin dependent kinase (CDK), CDK1. We are interested in a group of CDKs that are poorly characterized (CDK14-18) that might also contribute to the regulation of proliferation. Finally, mitosis is also controlled at the transcriptional level and we have identified RNA-binding proteins that are required for proliferation and whose depletion causes cells to arrest in mitosis.
Stephan Geley, Daniela Fankhauser