Institute of Biomedical and Biomolecular Science (IBBS)
Cellular Signalling
Our research primarily focuses on the biology and pathological significance of the
(i) Tensin family of intracellular proteins, as well as the
(ii) Gas6/Axl ligand-receptor system.
Tensins
These are multi-modular intracellular proteins that house C terminal SH2-PTB tandem domains, as well as, in Tensins1-3, a phosphatase domain homologous to that of the tumour suppressor PTEN.
The Tensin protein family and their domain organisations
Our lab cloned two variants of the human Tensin2 gene (TENC1), and we observed that the protein displayed similar phenotypic and signalling effects on cells as PTEN. We have also observed all four Tensins to be down-regulated in expression in human kidney cancer.
Tensin3 immunostaining in normal human kidney vs renal cell carcinoma sections. Brown staining indicated presence of Tensin3 protein, which is largely lost in clear cell carcinoma.
Moreover, these proteins have the additional properties of binding to growth factor receptors (such as Axl), integrins and tumour suppressors (such as DLC1). Through these interactions, the Tensins appear to coordinate amongst themselves the cytoskeletal architecture that underlies the potential for tumour cells to become motile and metastasise, while also potentially negatively regulating growth/survival signalling pathways.
The goal of our lab is to uncover the role the Tensin protein family in tumour progression and spread, in particular focussing on kidney cancer, for which we have excellent collaborative links. To this end, we are characterising each Tensin for cellular effects, downstream signalling, protein/membrane interactions, enzymatic activity, molecular structure, and mechanisms behind altered expression in tumours.
The Gas6/Axl system
Axl is a receptor tyrosine kinase of the same superfamily as the receptors for other growth factors EGF and PDGF. However, Axl has some molecular features not shared by other molecules that enable it to be oncogenic, and particularly pro-metastatic, in a unique way. Gas6 is a growth/survival factor that is the ligand for Axl, and is relatively unique in being a vitamin K-dependent protein, which is a property normally associated with blood coagulation factors. We have uncovered a number of protein interactions with Axl inside the cell, which may relay the effects of Gas6 binding and activation.
Gas6/protein S-Axl interaction on the cell surface leads to signalling for survival and/or growth. In addition, soluble Axl ectodomain liberated by extracellular protease action, can lead to formation of a soluble Gas6-Axl complex that blocks Gas6 ligand action.
Both Gas6 and Axl are present widely throughout the human body, and Axl has been shown to be overexpressed in many different cancers including the kidney and brain, which are tumours we are particularly working on. We have for a number of years been characterising the Gas6/Axl pathway, both in terms of its normal structure-function relationships, as well its altered expression/activity in diseases such as kidney cancer. We are currently further probing the effects of Gas6/Axl signalling on phenotypic characteristics including proliferation, adhesion and migration and on intracellular signal transduction. Recently, we have also turned out attention to the potential of the Gas6/Axl pathway to drive cell migration and invasion of glioma cells. Furthermore, we are also investigating novel selective Axl inhibition agents as potential anticancer therapies.
Techniques and Resources
Our work routinely involves cell culture, protein analysis by e.g. western blot, immunocytochemistry, confocal microscopy (see picture), cell assays for proliferation, migration, invasion and apoptosis. Molecular biology techniques are also common tools, including PCR, qRT-PCR, molecular cloning, mutagenesis and protein expression in vivo and in vitro. We also enjoy access to a wide array of technologies available to us within the IBBS as a whole, which covers everything from transgenic animal science to electron microscopy.
Axl immunofluorescent staining in human prostate cancer cells
| Group Members | ||
|---|---|---|
| Sassan Hafizi |
Group Leader |
Senior Lecturer in Pharmacology |
| Jessica Carter | PhD Student (funded by IBBS) | Characterisation of Tensin proteins and their roles in cancer cell migration |
| Salman Goudarzi | PhD student (funded by the MS Society; co-supervised with Prof. Arthur Butt) | Role of Gas6 as a positive regulator of myelination |
|
Mikaella Vouri
|
PhD student (funded by Headcase Cancer Trust; co-supervised with Dr. Qian An) | Role of the Gas6/Axl pathway in glioblastoma |
| Julia Sandmaier | Undergrad bachelor project (Furtwangen university, Germany) | DISC1 protein - protein interactions |
Previous Members
ERASMUS Interns - Philipp Staudacher, Desiree Ludwig, Regina Meyer, Léa Peyrolle, Steffen Schuetz, Claudia Schmidberger, David Kleinhansl
Research Assistant - Emma James
Wellcome Trust undergrad summer vacation scholarship 2011 and 2012 - Charlotte Ford, Matthew Parslow
