Distinct and overlapping functional roles of Src family kinases in mouse platelets.
OBJECTIVE
Src family kinases (SFKs) play a critical role in initiating and propagating signals in platelets. The aims of this study were to quantitate SFK members present in platelets and to analyze their contribution to platelet regulation using glycoprotein VI (GPVI) and intregrin αIIbβ3, and in vivo.


RESULTS
Mouse platelets express four SFKs, Fgr, Fyn, Lyn and Src, with Lyn expressed at a considerably higher level than the others. Using mutant mouse models, we demonstrate that platelet activation by collagen-related peptide (CRP) is delayed and then potentiated in the absence of Lyn, but only marginally reduced in the absence of Fyn or Fgr, and unaltered in the absence of Src. Compound deletions of Lyn/Src or Fyn/Lyn, but not of Fyn/Src or Fgr/Lyn, exhibit a greater delay in activation relative to Lyn-deficient platelets. Fibrinogen-adherent platelets show reduced spreading in the absence of Src, potentiation in the absence of Lyn, but no change in the absence of Fyn or Fgr. In mice double-deficient in Lyn/Src or Fgr/Lyn, the inhibitory role of Lyn on spreading on fibrinogen is lost. Lyn is the major SFK-mediating platelet aggregation on collagen at arterial shear and its absence leads to a reduction in thrombus size in a laser injury model.


CONCLUSIONS
These results demonstrate that SFKs share individual and overlapping roles in regulating platelet activation, with Lyn having a dual role in regulating GPVI signaling and an inhibitory role downstream of αIIbβ3, which requires prior signaling through Src.
Centre for Cardiovascular Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. sonia.severin@inserm.fr
S
S
Séverin
C A
CA
Nash
J
J
Mori
Y
Y
Zhao
C
C
Abram
C A
CA
Lowell
Y A
YA
Senis
S P
SP
Watson
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D002352:Carrier Proteins / Q000378:metabolism; D048430:Cell Shape; D004195:Disease Models, Animal; D005340:Fibrinogen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010455:Peptides / Q000378:metabolism; D015539:Platelet Activation / Q000235:genetics; D010973:Platelet Adhesiveness; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000097:blood; D051076:Proto-Oncogene Proteins c-fyn; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000201:enzymology / Q000235:genetics; D013997:Time Factors; D019061:src-Family Kinases / Q000097:blood* / Q000172:deficiency / Q000235:genetics
D002352:Carrier Proteins; D010455:Peptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; C435908:collagen-related peptide; C098341:platelet membrane glycoprotein VI; D005340:Fibrinogen; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases