Regulation of platelet signalling by the ITIM-containing receptor G6b-B

Geer, Mitchell Jon (2018). Regulation of platelet signalling by the ITIM-containing receptor G6b-B. University of Birmingham. Ph.D.

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Abstract

Platelets are anucleate blood cells that regulate haemostasis, thrombosis, and many other pathophysiological processes. Understanding the mechanisms controlling platelet function therefore has implications for multiple healthy and diseased states. The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is essential for normal platelet production and function. It is thought to signal through the protein tyrosine-phosphatases Shp1 and Shp2, which bind to phosphorylated tyrosine residues in G6b-B. The aim of this thesis was to better understand the signalling mechanism of human and mouse G6b-B. Recruitment of Shp1 and Shp2 was demonstrated to be essential for G6b-B function using a novel G6b knock-in mouse model, in which the tyrosine residues were replaced with phenylalanine. These mutations resulted in defective haemostasis, caused by reduced platelet production and altered platelet function, due to compensatory mechanisms in the absence of G6b-B signalling. The homologous physiological function of human and mouse G6b-B was also demonstrated by characterisation of a humanised G6b knock-in mouse model. Expression of the human gene rescued the defects observed upon deletion of mouse G6b.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):