Differential role of glycolipid-enriched membrane domains in glycoprotein VI- and integrin-mediated phospholipase Cgamma2 regulation in platelets.
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.
Wonerow
Peter
P
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. peter.wonerow@pharm.ox.ac.uk
Obergfell
Achim
A
Wilde
Jonathan I
JI
Bobe
Régis
R
Asazuma
Naoki
N
Brdicka
Tomás
T
Leo
Albrecht
A
Schraven
Burkhart
B
Horejsí
Václav
V
Shattil
Sanford J
SJ
Watson
Steve P
SP
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*
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