Glycoprotein receptor mediated regulation of platelet morphology

Calaminus, Simon (2007). Glycoprotein receptor mediated regulation of platelet morphology. University of Birmingham. Ph.D.

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Abstract

Spreading platelets sequentially form filopodia, lamellipodia, and stress fibres. This thesis demonstrates the formation of each actin structure in spread platelets, and in addition the formation of a novel actin structure, which I have termed an actin nodule. Actin nodules require Src kinase activation, and actin polymerisation, but are negatively correlated to ROCK and myosin-II activation.
This thesis has investigated the role of WAVE-l, Rho kinase (ROCK) and myosin-II in spreading and aggregate stability in vitro and in vivo. ROCK or myosin-II inhibition, prevents stress fibre formation leading to appearance of splits and holes (termed fenestrations) in spread platelets on collagen. In addition, ROCK or myosin-II inhibition compromises aggregate stability on collagen at arterial rates of flow. Lamellipodia formation is inhibited in WAVE-rl - platelets spread on CRP, whilst shape change and aggregation downstream of GPVI is severely disrupted. However, GPCR agonists induce full lamellipodia formation on fibrinogen in WAVE-I-I. Aggregate formation on collagen under arterial rates of flow is unaffected further indicating . WAVE-2 can compensate for WAVE-I. Thus, WAVE-l maybe differentially regulated downstream of GPCR and glycoprotein signalling.
The actin regulatory proteins, Spin-90, Β-Pix and Nck are tyrosine phosphorylated by multiple platelet agonists, but do not form a complex upon platelet adhesion. However, B-Pix is heavily phosphorylated downstream of the collagen receptor integrin, a2BI. I speculate B-Pix may play an important role in connecting PLCyl to Rac activation.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Supervisor(s):
Supervisor(s)EmailORCID
Watson, Steve P.UNSPECIFIEDUNSPECIFIED
Machesky, LauraUNSPECIFIEDUNSPECIFIED
Licence:
College/Faculty: Schools (1998 to 2008) > School of Medicine
School or Department: Institute of Cardiovascular Sciences
Funders: British Heart Foundation
Subjects: Q Science > QP Physiology
URI: http://etheses.bham.ac.uk/id/eprint/7203

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