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Transglutaminase 2 (TG2) in partnership-investigating TG2’s roles in cell communication

Primary Supervisor: Dr Vivian Wang, Life & Health Sciences

Secondary supervisors: Prof Andrew Devitt and Prof Danielle Sblattero (External, University of Trieste, Italy)

PhD project title: Transglutaminase 2 (TG2) in partnership-investigating TG2’s roles in cell communication

University of Registration: Aston University

Project outline:

Background

Transglutaminase 2 (TG2) is a well-established signalling molecule in various conditions, such as wound healing (Wang et al., 2012) and apoptotic cell clearance by macrophages (Nadella et al., 2014). TG2 is secreted into the extracellular environment by a non-conventional mechanism thought to require cell surface syndecan-4 where it mediates the crosslinking reaction of extracellular matrix proteins, such as fibronectin and collagen (Wang et al., 2012). TG2’s association with difference cell surface receptors are important in maintaining and regulating cell functions, such as cell adhesion, migration and signal communication between cells (Wang and Griffin, 2012).

Over recent years, extracellular vesicles (EV) have been identified as a novel intercellular communication mechanism (Van Niel et al., 2018). These membrane bags, released from cells during health, disease and cell death, carry many factors to recipient cells to elicit responses (desirable and non-desirable). Extracellular Vesicle (EV) It has been reported that TG2 is present within extracellular vesicle (EV) and plays an important role in cancer metastasis (Shinte et al, 2020). Our work preliminary suggests that TG2 is present in the EV from various cells and could be playing important roles in different physiological conditions, such as apoptotic cell clearance by macrophages.

Tools developed at Aston, including small molecule TG2 inhibitors (Badarau et al., 2015) and functional inhibiting antibodies, have allowed us to explore TG2’s association with its binding partner and the importance of this association in various biological events, such as cell migration and angiogenesis.

The aims of this project are:

  • To investigate the importance of TG2’s interaction with its cell surface binding partners in its secretion into the extracellular environment in various biological conditions, such as apoptosis
  • To confirm the presence of TG2 and its binding partners in EVs in different biological cell models, e.g. apoptotic cells, and their biological importance
  • To assess the effects of TG2 antagonists on regulating TG2’s interaction with its binding partner during TG2 externalization, including VE formation and secretion by apoptotic cells.

References:

  1. Shinde A, Paez JS, Libring S, Hopkins K, Solorio L and Wendt MK. Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche Oncogenesis (2020) 9:16 https://doi.org/10.1038/s41389-020-0204-5
  2. Van Niel G, D’Angelo G, and Raposo (2018). Shedding light on the cell biology of extracellular vesicles. Nature Reviews: Molecular Cell Biology: DOI: 10.1038/nrm.2017.12
  3. Wang Z and Griffin M. (2012) TG2, a novel extracellular protein with multiple functions. Amino Acids 42:939–949
  4. Wang Z, Collighan RJ, Pytel K, Rathbone DL, Li X, Griffin M. (2012) Characterization of heparin-binding site of tissue transglutaminase: its importance in cell surface targeting, matrix deposition, and cell signaling. J Biol Chem. 287(16):13063-83.
  5. Badarau E, Wang Z, Rathbone DL, Costanzi A, Thibault T, Murdoch CE, El Alaoui S, Barkeviciute M, Griffin M. (2015) Development of Potent and Selective Tissue Transglutaminase (TG2) Inhibitors― their effect on TG2 function and application in pathological conditions. Chemistry and Biology. 22: 1347–61

BBSRC Strategic Research Priority: Understanding the Rules of Life: Ageing

    Techniques that will be undertaken during the project:

    • Cell culture: Tissue culture of a range of cell lines and primary cells. Ex vivo culture of tissues. Co-culture system to study different biological events.
    • Vesicle analyses: isolation and analysis of EV structure and function using qNano tunable resistive pulse sensing, flow cytometry, electron microscopy, analysis of immune-modulating capability in vitro using chemoattraction assays and qPCR.
    • Imaging and analysis: Flow cytometry, light and fluorescence microscopy including real-time microscopy and confocal microscopy, automated cell imaging for functional studies

    Contact: Dr Vivian Wang, Aston University