title: Differential role of glycolipid-enriched membrane domains in glycoprotein VI- and integrin-mediated phospholipase Cgamma2 regulation in platelets.
abstract: The platelet collagen receptor glycoprotein VI (GPVI) and the fibrinogen receptor integrin alphaIIbbeta3 trigger intracellular signalling cascades involving the tyrosine kinase Syk, the adapter SLP-76 and phospholipase Cgamma2 (PLCgamma2). Similar pathways are activated downstream of immune receptors in lymphocytes, where they have been localized in part to glycolipid-enriched membrane domains (GEMs). Here we provide several lines of evidence that GPVI-mediated tyrosine phosphorylation of PLCgamma2 in platelets is dependent on GEM-organized signalling and utilizes the GEM resident adapter protein LAT (linker for activation of T cells). In sharp contrast, although fibrinogen binding to platelets stimulates alphaIIbbeta3-dependent activation of Syk and tyrosine phosphorylation of SLP-76 and PLCgamma2, it does not utilize GEMs to promote these responses or to support platelet aggregation. These results establish that GPVI and alphaIIbbeta3 trigger distinct patterns of receptor signalling in platelets, leading to tyrosine phosphorylation of PLCgamma2, and they highlight the role of GEMs in compartmentalizing signalling reactions involved in haemostasis.
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. peter.wonerow@pharm.ox.ac.uk
authors.forename: Peter
authors.initials: P
authors.lastname: Wonerow
authors.forename: Achim
authors.initials: A
authors.lastname: Obergfell
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Wilde
authors.forename: Régis
authors.initials: R
authors.lastname: Bobe
authors.forename: Naoki
authors.initials: N
authors.lastname: Asazuma
authors.forename: Tomás
authors.initials: T
authors.lastname: Brdicka
authors.forename: Albrecht
authors.initials: A
authors.lastname: Leo
authors.forename: Burkhart
authors.initials: B
authors.lastname: Schraven
authors.forename: Václav
authors.initials: V
authors.lastname: Horejsí
authors.forename: Sanford J
authors.initials: SJ
authors.lastname: Shattil
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
mesh_terms: D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000737:chemistry / Q000201:enzymology*; D005340:Fibrinogen / Q000494:pharmacology; D006017:Glycolipids / Q000097:blood; D006801:Humans; D007527:Isoenzymes / Q000097:blood*; D008563:Membrane Lipids / Q000097:blood; D051966:Phospholipase C gamma; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000494:pharmacology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000097:blood*
chemical_list: D006017:Glycolipids; D007527:Isoenzymes; D008563:Membrane Lipids; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D019000:Phosphotyrosine; D005340:Fibrinogen; D010738:Type C Phospholipases; D051966:Phospholipase C gamma