Cellular Signalling Group
Conducting cell and molecular biology research into growth factors and growth factor receptors
The cellular signalling group conducts cell and molecular biology research into growth factors and growth factor receptors, and what roles they play in health and in disease.
The group is lead by Dr Sassan Hafizi.
Our work focuses on the TAM (Tyro3, Axl, Mer) receptor tyrosine kinases, the ligands for which are two related vitamin K-dependent proteins, Gas6 and protein S. The TAM receptors activate signalling pathways within cells that regulate distinct functions in the body, including suppression of inflammation and the immune response, cell differentiation, remyelination in the brain, cancer cell invasion and metastasis, and even acting as decoy entry gateways for pathogenic microbes.
We are currently investigating the roles of TAM receptors in two distinct areas of pathology - neuroinflammation in neurodegenerative diseases (e.g. Alzheimer’s disease, multiple sclerosis (MS)) and cancer.
Since 2009, the Hafizi lab has trained 14 research students at PhD level so far, as well as MRes students on an annual basis. The group welcomes enquiries from potential applicants for PhD or MRes research degrees, working within one of the topics presented below.
Our current laboratory research
Gas6 and TAM receptors as suppressors of inflammation and stimulators of repair in neurodegenerative diseases
MS is an autoimmune condition that features chronic neuroinflammation, which causes damage to the myelin sheath around nerve cells in the CNS, thus impairing normal nerve electrical impulse transmission.
However, the CNS contains stem cells (oligodendrocyte precursor cells), which as part of a repair response could be activated to proliferate and form new cells that produce new myelin insulation for damaged nerves. In addition, the immune system also plays a part in provoking the damage to myelin during the progression of MS. Therefore, understanding the mechanisms that drive oligodendrocyte regeneration, as well as those that regulate the immune response and neuroinflammation in the brain could reveal novel targets for MS therapy.
Our recent research has shown that Gas6 is both as an inflammation suppressing molecule (e.g. dampening excessive microglial responses) as well as a repairing molecule (e.g. stimulating new myelination of exposed axons and astrocyte remodelling). We are currently studying these functions of Gas6 in MS but also in Alzheimer’s, as the latter condition also features chronic neuroinflammation, in which Gas6/TAMs also appear to be involved. In our laboratory, we carry out basic mechanistic research, utilising a range of cell biological and biochemical techniques, including in vitro cell culture, ex vivo brain tissue culture, molecular expression analyses, including transcriptomic and proteomic analyses, immunohistochemistry and confocal microscopy.
We also carry out clinical translational investigations, where we analyse alterations in Gas6 system components in clinical samples from tissue banks. This arm of our research has been funded by the MS Society and Hans Boeckler Foundation.
TAM receptors as mediators of cancer spread and resistance to chemotherapeutics
We are investigating the role of TAM receptors and their signalling in driving cancer cell behaviours, in particular cancer cell invasiveness and also conferring resistance to chemotherapeutic drugs, of which TAMs have been particularly noted as mediators.
Our research up to now has determined that Axl receptor is a driver of tumour cell invasion, and that it interacts with EGFR to enable the latter to activate discrete Axl intracellular signalling and thereby drive cancer cell invasion via Axl. We have more recently unravelled the mechanism of Tyro3 receptor function in cancer, where we have shown that Tyro3 activates distinct signalling pathways within cancer cells to Axl, when both are expressed in the same cells.
We have also probed the structural determinants of the Tyro3 receptor interaction with one of its ligands, protein S. Currently, we are also working on developing novel inhibitors of Tyro3 function as potential targeted cancer therapeutics.
For our work, we utilise a variety of experimental assays techniques, mostly based on cancer cell culture. Alongside the cellular and molecular experimentation, we also perform in silico molecular docking analysis to identify and characterise molecular interactions.
Tensin family of intracellular proteins
Our lab is also investigating the role of the Tensin protein family, which regulate the cytoskeleton and thereby cell architecture and motility.
The Tensins, composed of Tensin1, -2 , -3 and -4 (Cten), are multi-modular intracellular proteins that house C-terminal SH2-PTB domains, as well as, in Tensins1-3, a phosphatase domain homologous to that of the tumour suppressor phosphatase PTEN.
Our lab cloned two variants of the human Tensin2 gene (TNS2), and we observed that the protein displayed similar signalling and functional effects as PTEN phosphatase, commonly dysregulated in cancer. Moreover, these proteins have the additional properties of binding to growth factor receptors (such as Axl), integrins and tumour suppressors.
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 regulating cell growth/survival.
One of our aims is to uncover the mechanisms behind the roles of Tensins in tumour progression and spread.
Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiation
Merour, E., Hmidan, H., Marie, C., Helou, P., Lu, H., Potel, A., Hure, J., Clavairoly, A., Ping Shih, Y., Goudarzi, S., Dussaud, S., Ravassard, P., Hafizi, S., Hao Lo, S., Hassan, B.A., Parras, C. (2022) "Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiation", eLife
Gilchrist, S.E., Pennelli, G.M., Hafizi, S., (2021) "Gas6/TAM signalling negatively regulates inflammatory induction of GM-CSF in mouse brain microglia", Cells
The first laminin G-like domain of protein S is essential for binding and activation of Tyro3 receptor and intracellular signalling
Al Kafri, N., Ahnström, J., Teraz-Orosz, A., Chaput, L., Singh, N., Villoutreix, B.O., Hafizi, S. (2022) "The first laminin G-like domain of protein S is essential for binding and activation of Tyro3 receptor and intracellular signalling", Biochemistry and Biophysics Reports
Mainsiouw, L., Ryan, M., Hafizi, S., Fleming, J.C. (2023) "The molecular and clinical role of Tensin 1/2/3 in cancer", Journal of Cellular and Molecular Medicine