Institute of Biomedical and Biomolecular Science
Cellular Signalling Group
The Hafizi lab conducts cell and molecular biology research into growth factors and growth factor receptors, and what roles they play in health and in disease.
For further details and publication history please see my staff profile
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 other RTKs such as EGFR and Insulin receptor. The ligands for the TAMs are two homologous vitamin K-dependent proteins, Gas6 and protein S. In addition, we are investigating the intracellular signalling pathways downstream of TAM receptor activation.
The TAM receptors 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 mediating entry of pathogenic microbes into the cell. We are currently investigating the role of TAM receptors in two pathology 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.
We are investigating 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 ex vivo brain tissue culture, in vitro cell culture, molecular expression analyses, immunohistochemistry, 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 (see diagram below):
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
We are investigating the role of TAM receptor signalling in driving cancer cell invasion, utilising a variety of experimental assays. So far, we have determined that the Axl drives invasion of brain tumour cells through a discrete signalling mechanism, and that this can be blocked with selective small molecule inhibition. We have also uncovered an unconventional interaction between EGFR and Axl kinases; this hetero-interaction enables EGFR to activate Axl signalling and thereby drive cancer cell invasion.
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.
4) Mechanobiology of cardiac fibroblasts
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/myofibroblasts. 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 cardiac fibroblasts which, alongside molecular stimulation by growth factors and vasoactive molecules, respond to mechanical forces. This will include culture of cardiac fibroblasts and their characterisation for expression of a variety of established fibroblast markers, sequencing analysis to determine novel signature profiles, as well as the effects of mechanical force on these profiles.