Cunningham, Catherine Nicola; (1996) Studies on the role of the tyrosine kinase Lyn in B cell receptor signal transduction. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

B lymphocytes recognise and respond to antigens via the B-cell receptor (BCR) expressed on the cell surface. Ligation of the BCR leads to apoptosis, receptor endocytosis, antigen presentation, differentiation and proliferation, depending upon the developmental window of the B cell and the specificity of the antigen ligand. Although the BCR has no intrinsic enzymatic activity, tyrosine phosphorylation is the earliest detectable response to BCR stimulation. Cells of the hematopoietic system differentially express members of the Src family of tyrosine kinases, and these proteins have been shown to be associated with a variety of receptors in these cells. Notably Lck is physically and functionally associated with the T cell coreceptors CD4 and CD8, whilst Fyn is associated with the CD3 component of the T cell receptor. Likewise B cells express the Src family members Lyn, Blk and Fyn, all of which have been shown to associate with the BCR. The possible role of Lyn in signal transduction through the BCR was investigated. Mutational analysis is the most powerful method of assigning a function to a gene or protein; therefore expression vectors carrying either the the wild type Lyn or a kinase disabled mutant form of the gene were made. This was achieved by changing a critical lysine in the ATP binding site to a methionine residue, which it was anticipated would act as a dominant negative mutation when overexpressed. Seven lines of transgenic mice were generated, carrying a range of copy numbers of the mutant gene under the control of the immunoglobulin heavy chain enhancer. B cell compartments in these mice were analysed for expression of the transgene, and B cell development in the bone marrow was studied. Also the expression vectors were transfected into a B cell line in vitro in order to study the biochemistry of signalling through the BCR.

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