eTheses Repository

CD148: a positive regulator of GPVI and \(\alpha\)II\(\beta\)3 proximal signalling in platelets

Ellison, Stuart (2010)
Ph.D. thesis, University of Birmingham.

Loading
PDF (3784Kb)

Abstract

Platelets are small anucleate blood cells that plug holes in damage blood vessels. They do so by adhering to exposed extracellular matrix proteins at sites of injury and aggregating together. Platelet responsiveness to injury is controlled by a diverse repertoire of surface receptors that can be divided into two broad categories based on how they signal; the tyrosine kinased-linked receptors and the G protein-coupled receptors (GPCRs). There has been much work on elucidating the functions of tyrosine kinases in platelets, whereas protein tyrosine phosphatases (PTPs) have been under-investigated. To date, six non-transmembrane PTPs (NTPTPs), PTP-1B, Shp1, Shp2, MEG2-PTP, LMW-PTP and HePTP and a single receptor-like PTP (RPTP), CD148, have been identified in platelets. The main objective of this thesis was to determine the functional role of CD148 in platelets, which had never been studied in platelets. Using a mouse model, I demonstrate that CD148 is a critical positive regulator of signalling from the main collagen activation receptor GPVI and the fibrinogen integrin \(\alpha\)II\(\beta\)3, and also plays a minor role in regulating thrombin and thromboxane A\(_\\) (TxA\(_2\) mediated aggregation and secretion via the PAR-4 and TP receptors, respectively. The molecular mechanism of how CD148 regulates signalling from so many receptors is by maintaining a pool of active Src family kinases (SFKs) in platelets, which it does by dephosphorylating a tyrosine residue in the C-terminal of all SFKs. In an attempt to identify other PTPs that perform a similar function to CD148 in platelets, I analyzed platelets from PTP-1B- and TC-PTP-deficient mouse models for functional and phosphorylation defects. PTP-1B-deficient platelets exhibited minor aggregation/secretion and phosphorylation defects relative to CD148-deficient platelets; and TC-PTP, which I show to be expressed in human and mouse platelets for the first time, is involved in platelet development. My conclusion is that CD148, PTP-1B and TC-PTP have distinct functional roles in platelets.

Type of Work:Ph.D. thesis.
Supervisor(s):Senis, Yotis
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Medicine
Subjects:RC Internal medicine
Institution:University of Birmingham
ID Code:727
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
Export Reference As : ASCII + BibTeX + Dublin Core + EndNote + HTML + METS + MODS + OpenURL Object + Reference Manager + Refer + RefWorks
Share this item :
QR Code for this page

Repository Staff Only: item control page