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Molecular investigations into Btk and wasp

MacCarthy-Morrogh, Lucy; (1998) Molecular investigations into Btk and wasp. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Bruton's tyrosine kinase (Btk) is a modular non-receptor protein tyrosine kinase which when mutated results in the immunodeficiency X-linked agammaglobulinemia (XLA) in man and xid in mice. The disease is characterised by a block in the development of B cells and as a consequence, levels of serum immunoglobulin of all isotypes are reduced. Btk is therefore crucial for B cell development. It is also implicated in the transduction of signals in both developing and mature B cells. In humans, Btk has only been reported to be stimulated on ligation of the B cell receptor (BCR), and investigations in this thesis were performed in order to ascertain whether Btk activation is induced upon ligation of the cell surface receptors CD22 and CD38, as might be expected due to the nature of the XLA phenotype. The modular nature of the Btk protein led to investigations into ligands of these domains in order to determine possible in vitro ligands of Btk. This thesis presents studies of the SH3 domains of Btk, Itk and Tec, expressed as GST fusion proteins. The SH3 domains of all three proteins were seen to bind a similar set of proteins in B cell lysates including the proteins previously identified as Btk SH3 domain in vitro ligands, WASP and c-Cbl. Auto-phosphorylation of the Btk SH3 domain fusion protein led to altered ligand binding. A tyrosine phosphorylated protein observed to bind the phosphorylated but not the unphosphorylated Btk SH3 domain fusion protein was identified as another protein tyrosine kinase, Syk. The identification of WASP, mutated in patients suffering from another X-linked immunodeficiency, the Wiskott-Aldrich Syndrome (WAS), as an in vitro ligand of Btk, led to investigations into the expression of WASP in WAS patients. Results show that no patients with severe WAS in the study expressed WASP at detectable levels, irrespective of the nature or position of the mutation characterised in these patients.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Molecular investigations into Btk and wasp
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10100040
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