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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-06-1847.
Submitted June 24, 2002
Accepted December 13, 2002
Role of the intracellular domains of GPIb in controlling the adhesive properties of the platelet GPIb/V/IX complex
Christelle Perrault, Pierre Mangin, Martine Santer, Marie-Jeanne Baas, Sylvie Moog, Susan L Cranmer, Inna Pikovski, David Williamson, Shaun P Jackson, Jean-Pierre Cazenave, and Francois Lanza*
INSERM, Unite 311-EFS-Alsace, Strasbourg, France
Australian Centre for Blood Diseases, Monash Medical School, Melbourne, VIC, Australia
* Corresponding author; email: francois.lanza{at}efs-alsace.fr.
GPIb/V/IX complex-dependent platelet adhesion to von Willebrand factor (vWF) is supported by the 45 kDa N-terminal extracellular domain of the GPIb subunit. Recent results with an adhesion blocking antibody (RAM.1) against GPIb , which is disulfide-linked to GPIb, have suggested a novel function of this subunit in regulating vWF-mediated platelet adhesion, possibly involving its intracellular face. A putative cooperation between the GPIb and GPIb cytoplasmic domains was investigated by measuring the adhesion under flow to immobilised vWF of K562 and CHO cells transfected with GPIb/(V)/IX containing mutations in this region. Adhesion of cells carrying a Gly substitution of the GPIb Ser166 phosphorylation site was 50% lower than normal and became insensitive to inhibition by RAM.1. In contrast, forskolin or PGE1 treatment increased both the phosphorylation of GPIb and the adhesion of control cells, both effects being reversed by RAM.1. Neither treatment had any effect on cells expressing the Ser166 to Gly mutation. A role of the GPIb intracellular domain was also apparent as the vWF-dependent adhesion of cells containing deletions of the entire ( 518-610) or portions (535-568, 569-610) of the GPIb cytoplasmic tail was insensitive to RAM.1 inhibition. Cells carrying progressive 11 amino acid deletions spanning the GPIb 535-590 region were equally unresponsive to RAM.1, with the exception of those containing GPIb 569-579 which behaved like control cells. These findings support a role of the GPIb intracellular domain in controlling the adhesive properties of the GPIb/V/IX complex through phosphorylation of GPIb Ser166 and point to the existence of cross-talk between the GPIb and GPIb intracellular domains.
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