TULA-2 Protein Phosphatase Suppresses Activation of Syk through the GPVI Platelet Receptor for Collagen by Dephosphorylating Tyr(P)346, a Regulatory Site of Syk.
Protein-tyrosine phosphatase TULA-2 has been shown to regulate receptor signaling in several cell types, including platelets. Platelets are critical for maintaining vascular integrity; this function is mediated by platelet aggregation in response to recognition of the exposed basement membrane collagen by the GPVI receptor, which is non-covalently associated with the signal-transducing FcRγ polypeptide chain. Our previous studies suggested that TULA-2 plays an important role in negatively regulating signaling through GPVI-FcRγ and indicated that the tyrosine-protein kinase Syk is a key target of the regulatory action of TULA-2 in platelets. However, the molecular basis of the down-regulatory effect of TULA-2 on Syk activation via FcRγ remained unclear. In this study, we demonstrate that suppression of Syk activation by TULA-2 is mediated, to a substantial degree, by dephosphorylation of Tyr(P)346, a regulatory site of Syk, which becomes phosphorylated soon after receptor ligation and plays a critical role in initiating the process that yields fully activated Syk. TULA-2 is capable of dephosphorylating Tyr(P)346with high efficiency, thus controlling the overall activation of Syk, but is less efficient in dephosphorylating other regulatory sites of this kinase. Therefore, dephosphorylation of Tyr(P)346may be considered an important "checkpoint" in the regulation of Syk activation process. Putative biological functions of TULA-2-mediated dephosphorylation of Tyr(P)346may include deactivation of receptor-activated Syk or suppression of Syk activation by suboptimal stimulation.
From the Departments of Microbiology and Immunology and.|Ernst-Moritz-Arndt-University Greifswald, 17489 Greifswald, Germany.
Kevin
K
Reppschläger
From the Departments of Microbiology and Immunology and.|Polytech Clermont-Ferrand, Ingenieur Genie Biologique, Clermont-Ferrand, Auvergne 63178, France, and.
Jeanne
J
Gosselin
the Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140.
Carol A
CA
Dangelmaier
the Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140.|PMV Pharmaceuticals, Cranbury Township, New Jersey 08512.
Dafydd H
DH
Thomas
the Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794.
Nick
N
Carpino
the Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Steven E
SE
McKenzie
the Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140.|Physiology and.
Satya P
SP
Kunapuli
From the Departments of Microbiology and Immunology and tsygan@temple.edu.|the Sol Sherry Thrombosis Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140.
Alexander Y
AY
Tsygankov
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D000072377:Syk Kinase / Q000235:genetics / Q000378:metabolism*
D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D017027:Protein Tyrosine Phosphatases; C553497:TULA-2 protein, mouse
GPVI receptor; ITAM; TULA-2; platelet; protein phosphorylation; signaling; spleen tyrosine kinase (Syk); tyrosine-protein kinase (tyrosine kinase); tyrosine-protein phosphatase (tyrosine phosphatase)