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Research areas:

Key words: Endoplasmic reticulum, Proteostasis, Golgi apparatus, COPII, Kinases, Phosphatases, Rho-GTPases, Cell migration, breast cancer, multiple myeloma, Parkinson’s disease, Protein Aggregation, Mitosis, Ubiquitin, F-box proteins, Pseudophosphatase, Pseudoenzyme, Ubiquitin ligases, mitosis, aneuploidy, cancer, RNA degradation, cell division

  1. Regulation of Endoplasmic reticulum export:

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 how export from the ER is regulated by cellular signaling pathways such as kinases, phosphatases and small GTPases. We focus on signals in response to changes in the availability of mitogens or nutrients in the environment. In addition, we are characterizing signaling molecules resident to the ER and their role in autoregulation of ER-export. 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.

  1. Role of trafficking from the ER in alpha-Synuclein aggregation:

Lewy bodies are a hallmark of Parkinson’s disease and the basis for their formation is the aggregation of a protein called alpha-synculein. There is accumulating evidence that aggregates of alpha-synuclein and Lewy bodies contain organelles and membranous material. However, there is no causal relationship between the endomembrane system and the biogenesis of Lewy bodies. We are investigating how specialized subdomains on the ER that are referred to as ER exit sites (ERES) contribute to the aggregation of alpha-synuclein. Thereby, we expect to obtain mechanistic insight into the biogenesis of Lewy bodies.   

  1. Role of the Golgi in cancer cell migration tumor growth and metastasis:

The Golgi apparatus is composed of a stack of flattened cisternae located in the center of the cell in close association with the centrosome. The canonical functions of the Golgi include post-translational modification and sorting of secretory proteins. In addition, the Golgi is known to play a key role in cell migration. We are interested in how alterations of Golgi structure affect cell migration and invasion and how this in turn contributes to growth of tumors and their metastatic potential. To this end, we are investigating the structure of the Golgi in breast cancer samples to obtain quantitative information about the degree of Golgi alterations in patient material in dependence of breast cancer subtypes. To study the migration of breast cancer cells, we have developed an in-house tool to track moving cells. Finally, we are building computational models to simulate the growth and intravasation of breast cancer cells in dependence of different migration traits (e.g. persistence or speed). Overall, our goal is to understand how different types of cell migration that are associated with Golgi alterations contribute to the growth of a tumor.

  1. 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.

  1. 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 AP/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.

Institut für Pathophysiologie

Administration:

Claudia Ram
Tel: +43-512-9003-71400
Email: Claudia.ram@i-med.ac.at

Administration:

Claudia Ram
Tel: +43-512-9003-71400
Email: Claudia.ram@i-med.ac.at