Dr Kai Erdmann
Department of Biomedical Science
and the Centre for Membrane Interactions and Dynamics (CMIAD)
The University of Sheffield
Sheffield S10 2TN
Telephone: +44 (0) 114 222 4698
Membrane trafficking and signalling in polarised cells. Role of multi-PDZ domain proteins in cancer formation, metastasis and tumor invasion.
My group is part of the Centre for Membrane Interactions and Dynamics (CMIAD)
Biochemical and mechanochemical mechanisms of epithelial cell polarisation
Cell polarity is at the crossroads of differentiation and growth, and loss of cell polarity is a hallmark of cancer and other relevant diseases. Our group is interested in the regulation of cell polarization and its relation to human diseases. In particular, we analyze the molecular function of multi-PDZ domain proteins (PTPN13/PTP-BL and FRMPD2) in epithelial cell polarization as well as their role in cancer development and progression. PTPN13 and FRMPD2 are closely related and represent members of a small family of peripheral membrane proteins containing multiple PDZ domains as well as a FERM domain.
Both proteins are strongly expressed in epithelial cells. PTPN13 assembles an apical protein complex, whereas FRMPD2 organizes a protein complex at the basolateral membrane in epithelial cells. PTPN13 is involved in carcinogenesis and mediates resistance to Fas induced apoptosis by an unknown mechanism. FRMPD2 has recently been identified by our group and plays a role in cell/cell adhesion regulation. We are identifying PTPN13- and FRMPD2- protein complexes and based on this suggesting a potential role in intracellular membrane trafficking and cell adhesion for both proteins.
We analyze corresponding molecular mechanisms of cell polarization in 2D and 3D epithelial cell culture systems and have recently introduced chip-based micropatterning to control cell polarization by mechanical means. In addition, we analyze our target proteins in vivo using zebra fish as a model system.
Postgraduate PhD Opportunities
1. Establishment of an in vitro model for cystic fibrosis using organ on chip technology
Cystic fibrosis is a devastating disease affecting the lung and the intestine. Cystic fibrosis is a genetic disease and caused by mutations of the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator). Major phenotypes are increased mucus production in the lung causing extreme breathing difficulties as well as defective signaling in the intestine. One in three thousand newborns are affected.
The goal of this PhD project is the establishment of a state of the art in vitro model for cystic fibrosis to study the disease mechanism in more detail but also to establish a model suitable for high-throughput drug screening. The project will make use of modern organ on chip technology, which allows the functional reconstitution of organ functionality in miniaturized microfluidic devises. Precisely we will apply devices to mimic blood and airflow of the lung allowing a more physiological model system than just 2 or 3D cell cultures.
The aims of this project are
Techniques: CRISPR-technology, organoids, 3D cell cultures with different mechanical properties, micro-molding using soft-litography, Micropatterning, siRNA-technology, Cell imaging (live confocal spinning disk and super-resolution microscopy, Total-internal reflection microscopy)
2. The role of multi-PDZ domain proteins in the regulation of epithelial cell proliferation and cancer
PTPN13 is a highly modular multi-PDZ domain protein composed of an N-terminal KIND (Kinase non catalytic C-lobe) domain, followed by a FERM (Four-point-one/Ezrin/Radixin/Moesin) domain, five PDZ domains, and a tyrosine phosphatase domain assembling a large macromolecular protein complex. There is strong evidence that PTPN13 plays a role in tumor development. In a search for protein tyrosine phosphatases involved in formation of colon carcinoma, it was demonstrated that PTPN13 is mutated in around 10% of colon carcinomas. We have recently identified novel components of the PTPN13 complex. This complex plays an important role in the regulation of cell/cell adhesion and nuclear transcription. However, the precise molecular mechanism, how PTPN13 contributes to tumor development is largely unclear
The goal of this project is to investigate the role of PTPN13 and other multi-PDZ domain proteins in the context of contact inhibition of proliferation, metastasis and tumor invasion. We will apply in vitro cell proliferation, migration and tumor invasion assays as well as state of the art still- and live-imaging microscopy techniques (like spinning disc confocal microscopy and superresolution microscopy) to investigate underlying disease mechanisms. Furthermore, using in vitro 3-dimensional cell culture systems and modern chip based cell micropatterning we will further analyze the role and molecular mechanism of PTPN13 in epithelial cell proliferation and cell polarization.
For further information about these projects and how to apply, see our PhD Opportunities page:
Group leader: Dr. Kai Erdmann, e-mail: firstname.lastname@example.org
Lab phone extension is: 22364
EU Marie Curie-CIG-project Endosignal
Inflammatory bowel disease is a devastating disease affecting several million people in Europe. This project addresses the molecular mechanism of inflammatory bowel disease. The multi-PDZ domain protein FRMPD2 (FERM and PDZ domain containing protein 2) has been shown to be an integral part of the immune host defense of epithelial cells by recruiting NOD2 (Nucleotide-binding and oligomerization protein 2), a key player of the innate immune system, to the basolateral membrane in epithelial cells.
In addition, FRMPD2 is involved in epithelial cell/cell adhesion regulating tight junction formation. Interaction of NOD2 with FRMPD2 places the NOD2 protein into a novel context being part of a larger protein complex. Using an interdisciplinary approach combining state of the art techniques from cell biology, protein chemistry, membrane physics and developmental genetics, this project aims at the identification and functional characterization of novel components of the FRMPD2 protein complex.
In particular, this protein complex will be characterized with respect to mechanisms relevant to epithelial cell polarization and inflammatory bowel disease. Finally, the project aims to complement in vitro mechanistic and cell culture data with in vivo results by analyzing the role of the FRMPD2 complex in zebrafish development. The results of this project will lead to a better molecular understanding of the disease opening potentially new avenues of treatments.