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


College of Medical and Dental Sciences

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Prof S P Watson , Dr J Pike , Prof D Owen No more applications being accepted Funded PhD Project (Students Worldwide)

About the Project

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 develop complementary 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.

To apply for this project, please visit our website: https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx

Funding Notes

Stipend: RCUK standard rate (plus additional travel allowance in year 1 and a laptop). The Midlands Integrative Biosciences Training Partnership 2020 (MIBTP2020) is a BBSRC-funded doctoral training partnership between the Universities of Warwick, Birmingham, Leicester, Aston and Harper Adams. Awards for both UK residents and International applicants cover UK tuition fees and provide a stipend at the standard UKRI rate to support living costs. UKRI funding will not cover international fees.

References

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 Receptor Exhibit Differential Dependence upon Syk and Src family kinases. Science Signaling: 6 (256), ra1. DOI: 10.1126/scisignal.2003220

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
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