Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling.
Mice deficient in the adaptor Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) exhibit a bleeding disorder and lack T cells. Linker for activation of T cells (LAT)-deficient mice exhibit a similar T cell phenotype, but show no signs of hemorrhage. Both SLP-76 and LAT are important for optimal platelet activation downstream of the collagen receptor, GPVI. In addition, SLP-76 is involved in signaling mediated by integrin alphaIIbbeta3. Because SLP-76 and LAT function coordinately in T cell signal transduction, yet their roles appear to differ in hemostasis, we investigated in detail the functional consequences of SLP-76 and LAT deficiencies in platelets. Previously we have shown that LAT(-/-) platelets exhibit defective responses to the GPVI-specific agonist, collagen-related peptide (CRP). Consistent with this, we find that surface expression of P-selectin in response to high concentrations of GPVI ligands is reduced in both LAT- and SLP-76-deficient platelets. However, platelets from LAT(-/-) mice, but not SLP-76(-/-) mice, aggregate normally in response to high concentrations of collagen and convulxin. Additionally, unlike SLP-76, LAT is not tyrosine phosphorylated after fibrinogen binding to integrin alphaIIbbeta3, and collagen-stimulated platelets deficient in LAT spread normally on fibrinogen-coated surfaces. Together, these findings indicate that while LAT and SLP-76 are equally required for signaling via the T cell antigen receptor (TCR) and pre-TCR, platelet activation downstream of GPVI and alphaIIbbeta3 shows a much greater dependency on SLP-76 than LAT.
Judd
Barbi A
BA
Program in Molecular Biology, University of Iowa, Iowa City, IA 52242, USA.
Myung
Peggy S
PS
Obergfell
Achim
A
Myers
Erin E
EE
Cheng
Alec M
AM
Watson
Stephen P
SP
Pear
Warren S
WS
Allman
David
D
Shattil
Sanford J
SJ
Koretzky
Gary A
GA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology*; D010974:Platelet Aggregation / Q000235:genetics; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology; D010980:Platelet Membrane Glycoproteins / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C110810:LAT protein, human; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C092947:SLP-76 signal Transducing adaptor proteins; C098341:platelet membrane glycoprotein VI