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Mechanism of signalling by tyrosine kinase receptors in platelets and T cells

Primary Supervisor: Professor Steve Watson, Institute of Cardiovascular Sciences

Secondary supervisors: Dylan Owen, Jeremy Pike

PhD project title: Mechanism of signalling by tyrosine kinase receptors in platelets and T cells

University of Registration: University of Birmingham

Project outline:

The T cell antigen receptor (TCR) and the platelet immune receptors GPVI, CLEC-2 and PEAR1 signal through Src tyrosine kinase-regulated signalling pathways but in distinct ways. The TCR and GPVI signal though an ITAM which is a dual YxxL (Y = tyrosine) motif, with the conserved tyrosines phosphorylated by Src kinases. The TCR has ten ITAMs which provides 20 tyrosines for phosphorylation. GPVI has four copies of an ITAM which provides 8 tyrosines for phosphorylation. CLEC-2 has a single YxxL sequence (known as a hemITAM) which provides one tyrosine for phosphorylation. Yet all three receptors signal through a similar pathway which culminates in the activation of phospholipase C. In contrast, PEAR1 has a YxxM motif, with the conserved tyrosine being phosphorylated by Src kinases. PEAR1 signals via PI 3- kinase.

For all four receptors, it is assumed that ligand engagement generates a critical density of tyrosines in the membrane for phosphorylation by constitutively active Src kinases. However, each receptor needs a different degree of ligand valency to achieve activation, ranging from monomeric (T cell), dimeric (GPVI) and multimeric (CLEC-2 and PEAR1). The questions posed in this proposal are (i) what is the basis of the difference in signalling between the four receptors? and (ii) why do the receptors require different levels of clustering to achieve activation?

We will address these questions by modelling receptor activation using ordinary and partial differential equations and agent-based modelling, and developcomplementary spatial models which utilise machine learning and statistical tools. Data for these studies will be provided by protein biochemistry and advanced microscopy. The degree of experimental work will be tailored to the experience and background of the candidate.

The team of supervisors are specialists in platelet receptors (Watson), T cell receptor (Owen), advanced microscopy (Owen, Watson and Pike) and mathematical modelling (Owen and Pike).

The project is suitable for a student who wishes to work at the interface of biology and mathematics. They will join a multi- and inter-disciplinary group working on the immune function of platelets and T cells.

References:

  1. Mukherjee S, Zhu J, Zikherman J, Parameswaran R, Kadlecek TA, Wang Qi, Au-Yeung B, Ploegh H, Kuriyan J, Das J and Weiss A (2013) Monovalent and Multivalent Ligation of the B Cell
  2. Receptor Exhibit Differential Dependence upon Syk and Src family kinases. Science Signaling: 6 (256), ra1. DOI: 10.1126/scisignal.2003220
  3. Clemens L, Dushek O and Allard J (2020) Intrinsic disorder in the T cell receptor creates cooperativity and controls ZAP70 binding. BiorXiv https://doi.org/10.1101/2020.05.21.108662

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

    Techniques that will be undertaken during the project:

    The project will combine modelling, protein biochemistry and advanced microscopy:

    • Modelling:
    • Biochemistry: Microscopy:
    • Ordinary and partial differential equations; agent-based modelling; machine learning; statistical methods
    • Protein phosphorylation; enzyme assays
    • Single molecular microscopy; fluorescence correlation spectroscopy (FCS) subcellular light sheet

    Contact: Professor Steve Watson, University of Birmingham