Institute of Biomedical and Biomolecular Science
Cellular Signalling Group
The Hafizi lab is a cell and molecular biology research group that investigates how growth factors and growth factor receptors regulate cell behaviour in health and in disease.
For further details and publication history please see my staff profile
Molecular and Cellular Biology of Growth Factors and Their Receptors
Our research is focused in particular on the TAM (Tyro3, Axl, Mer) family of growth factor receptors (receptor tyrosine kinases; RTKs), which are in the same superfamily as the receptors for other growth factors such as EGF and PDGF. The natural ligands for the TAMs are two closely related vitamin K-dependent proteins, Gas6 (regulates cell survival, immunity and cell adhesion) and protein S (regulates the blood coagulation cascade). In addition, we are investigating the intracellular signalling pathways that emanate from TAM receptor activation, which amongst others includes the Tensin family of intracellular signalling molecules.
What distinguishes the TAM receptors as RTKs is that they activate signalling pathways that mediate a diverse set of influences in the body, including cell differentiation, remyelination in the brain, suppression of the immune system, cancer cell invasion and metastasis, and even covertly mediating entry of microbes into the cell during pathogenic infection. We are currently investigating the role of TAM receptors in two disease scenarios areas: (1) Multiple sclerosis (MS) and (2) cancer.
1) TAM receptors as mediators of remyelination and repair in MS
MS is a condition caused by damage to oligodendrocytes, the specialised myelin-forming glial cells in the CNS, thus impairing normal nerve electrical impulse transmission. However, the CNS contains stem cells, which could be activated to proliferate and form new oligodendrocytes as part of a repair response that produces 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 regulate the immune response in the brain could provide novel targets for MS therapy.
In collaboration with Prof Arthur Butt, we have been studying the role of Gas6 as a novel regulator of myelination in the brain, both in terms of promoting remodelling/repair after damage as well as dampening the immune response to prevent further damage. In our experiments, we utilise a range of cell biological and biochemical techniques, including in vitro cell culture, ex vivo tissue sampling and culture, molecular expression analyses, immunohistochemical techniques, confocal microscopy, and genomic and proteomic analyses. In our investigations far, we have determined that Gas6 activates multiple signalling pathways in different cells to stimulate the overall outcome of repair and regeneration in the brain:
Overview of our findings on the glial cells and molecular pathways activated by Gas6 in the brain (Goudarzi et al. 2016).
This research has been funded by the MS Society.
Recent publications from this work:
Goudarzi S, Rivera A, Butt AM and Hafizi S. Gas6 promotes oligodendrogenesis and myelination in the adult CNS and after lysolecithin-induced demyelination (2016). ASN Neuro. doi:10.1177/1759091416668430. View publication
2) TAM receptors as mediators of cancer cell invasion
Gliomas are a type of adult brain tumour notorious for their rapid development, high tissue infiltration and overall dismal prognosis. Therefore, there is a major need to understand the unique biology of these tumours, and in particular the mechanisms by which they spread through invading the brain tissue. We are currently investigating the role of TAM receptor signalling in driving brain tumour cell invasion, utilising both in vitro and in vivo models and a variety of experimental assays.
These studies are being conducted in collaboration with Prof Geoff Pilkington of the Brain Tumour Research Centre of Excellence Programme at Portsmouth and Prof Rolf Bjerkvig of the University of Bergen, Norway. So far, we have determined that the Axl RTK drives invasion of glioma cells through a discrete signalling mechanism, and that this can be blocked with selective small molecule inhibition
Recent publications from this work:
1) Vouri M, An Q, Birt M, Pilkington GJ and Hafizi S. Small molecule inhibition of Axl receptor tyrosine kinase potently suppresses multiple malignant properties of glioma cells (2015). Oncotarget. 6:16183-16197. View publication
2) Vouri M, Croucher DR, Kennedy SP, An Q, Pilkington GJ, and Hafizi S. Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells (2016). Oncogenesis 5, e266; doi:10.1038/oncsis.2016.66. View publication
3) Vouri M and Hafizi S. TAM receptor tyrosine kinases in cancer drug resistance (2017). Cancer Research doi: 10.1158/0008-5472.CAN-16-2675. View publication
Image - Axl overexpression (red fluoresence) in prostate cancer cells
3) Tensin family of intracellular proteins
Our lab is also investigating the role of the Tensin protein family, which are thought to 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 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.
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 role of Tensins in tumour progression and spread. 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.
In addition, while it is known that some Tensins are expressed in the brain, no knowledge currently exists as to their specific expression profiles in the brain, nor what functional roles they may play in the CNS. Therefore, another aim of ours, in collaboration with Dr Jerome Swinny, is to determine the expression profile of Tensins throughout the brain and through brain development, and especially to delineate the particular cell populations in which Tensins are expressed. This would lead to neurobiology studies investigating the roles of Tensins in neuronal architecture, plasticity and neurotransmitter release and storage.
4) Mechanobiology of cardiac interstitial cells
As an approach to studying cell biology in a more natural environment, we are also interested in the interplay between humoral factors, such as growth factors, and mechanical factors in regulating the dynamics of cells within tissues. Apart from myocytes and vascular cells, the heart is also composed in large part of fibroblasts, also known as interstitial cells (ICs). These are dynamic cells, with the ability to sense and respond to the environment profoundly in a variety of ways, e.g. differentiation, proliferation, matrix secretion and contraction. Therefore, we are investigating the molecular characteristics of ICs of the heart and of the aortic valves, both of which respond to major mechanical forces alongside molecular stimulation by growth factors and vasoactive molecules. We aim to isolate in culture ICs from the heart and aortic valves, and characterise them for expression of a variety of established fibroblast markers, as well as conduct high throughput sequencing analysis to determine novel signature profiles. This will also involve expression analyses on tissue sections and extracts, as well as measuring the biomechanical properties of the cells using special stretch/strain models. This latter aspect is conducted in collaboration with Dr Afshin Anssari-Benam of the University’s School of Engineering.
For PhD opportunities in any of the above project areas, we would be happy to hear from interested graduates with a minimum 2:1 degree with a molecular bioscience component (eg biochemistry, pharmacology, molecular biology, biomedical science).
We also invite expressions of interest from suitable PhD graduates who are interested in doing a postdoc, and who would themselves apply for a Fellowship opportunity.