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Signalling pathways controlling B cell survival

Project supervisor: Victor Tybulewicz (Immune Cell Biology)

In the adult mammal, the total number of naïve B cells is kept constant despite continuous influx of new B cells from the bone marrow and continuous recruitment of B cells into immune responses resulting in their differentiation into germinal centre B cells, plasma cells and memory B cells. This homeostasis of B cells is controlled by signals from two receptors: BAFFR and the B cell antigen receptor (BCR). BAFFR is a member of the TNF receptor family and binds the cytokine BAFF. We have recently found that rather than delivering standalone survival signals the receptors work closely together. In particular we discovered that BAFF binding to BAFFR results in phosphorylation of subunits of the BCR, and subsequently activation of the Syk tyrosine kinase, which transduces signals that are absolutely essential for B cell survival (Schweighoffer et al 2013).

This novel discovery of the close collaboration between these two seemingly unrelated receptors is the focus of the proposed project, whose aim will be to elucidate the mechanism by which BAFFR transduces signals to the BCR. The work will involve a combination of genetic and biochemical approaches in order to investigate both known BAFFR signalling pathways and to search for novel signal transducers acting downstream of the receptor. The student will use retroviral-based genetic complementation to identify regions of BAFFR required for the activation of Syk and will use proteomic methods to look for novel interaction partners for BAFFR. Inducible gene targeting will be used to evaluate the roles of signal transducers known to act downstream of BAFFR such as TRAF3, NIK and IKK1, in the pathways leading to Syk activation.

This work will be carried out at the MRC NIMR in the group of Victor Tybulewicz, in collaboration with GSK. Further information is available from Dr Tybulewicz

The post is a BBSRC case award funded for four years from October 2013, and the stipend is £20,000 per annum including London allowance. BBSRC eligibility criteria apply

To apply please download and complete the application form from the downloads section on the right-hand side. This position will remain open until a suitable applicant is appointed. Please apply early to avoid disappointment. Due to the high volume of applications we receive we are unable to provide feedback. If you do not hear from us within three weeks of application you have not been successful on this occasion.

Completed application forms should be returned to student@nimr.mrc.ac.uk

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Binding of BAFF to BAFFR results in phosphorylation of tyrosines in the ITAM motifs of the BCR, which in turn bind Syk, activating its kinase activity. Syk transduces signals through the ERK kinase and PI3 kinase (PI3K) pathways required for survival of B cells. Independently of this, BAFFR also transduces survival signals through IKK1 and NFκB2.

References

Schweighoffer, E., Vanes, L., Nys, J., Cantrell, D., McCleary, S., Smithers, N., and Tybulewicz, V. (2013). The BAFF receptor transduces survival signals by co-opting the B cell receptor signaling pathway. Immunity epub ahead of print.