Fyn and Lyn phosphorylate the Fc receptor gamma chain downstream of glycoprotein VI in murine platelets, and Lyn regulates a novel feedback pathway.
Activation of platelets by collagen is mediated by the complex glycoprotein VI (GPVI)/Fc receptor gamma (FcR gamma chain). In the current study, the role of 2 Src family kinases, Fyn and Lyn, in GPVI signaling has been examined using murine platelets deficient in one or both kinases. In the fyn(-/-) platelets, tyrosine phosphorylation of FcR gamma chain, phopholipase C (PLC) activity, aggregation, and secretion are reduced, though the time of onset of response is unchanged. In the lyn(-/-) platelets, there is a delay of up to 30 seconds in the onset of tyrosine phosphorylation and functional responses, followed by recovery of phosphorylation and potentiation of aggregation and alpha-granule secretion. Tyrosine phosphorylation and aggregation in response to stimulation by collagen-related peptide is further attenuated and delayed in fyn(-/-)lyn(-/-) double-mutant platelets, and potentiation is not seen. This study provides the first genetic evidence that Fyn and Lyn mediate FcR immune receptor tyrosine-based activation motif phosphorylation and PLC gamma 2 activation after the ligation of GPVI. Lyn plays an additional role in inhibiting platelet activation through an uncharacterized inhibitory pathway. (Blood. 2000;96:4246-4253)
Quek
L S
LS
Department of Pharmacology, University of Oxford, United Kingdom.
Pasquet
J M
JM
Hers
I
I
Cornall
R
R
Knight
G
G
Barnes
M
M
Hibbs
M L
ML
Dunn
A R
AR
Lowell
C A
CA
Watson
S P
SP
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins; D003094:Collagen / Q000494:pharmacology; D005246:Feedback; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051966:Phospholipase C gamma; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011506:Proteins / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism; D019061:src-Family Kinases / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology
D002352:Carrier Proteins; D007527:Isoenzymes; D010980:Platelet Membrane Glycoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; C007105:c1q-binding proteins; C098341:platelet membrane glycoprotein VI; D003094:Collagen; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma