title: TULA-2 (T-Cell Ubiquitin Ligand-2) Inhibits the Platelet Fc Receptor for IgG IIA (FcγRIIA) Signaling Pathway and Heparin-Induced Thrombocytopenia in Mice.
abstract: OBJECTIVE
  The objective of this study is to investigate the role of T-cell ubiquitin ligand-2 (TULA-2) in the platelet Fc receptor for IgG IIA (FcγRIIA) pathway and in the pathogenesis of heparin-induced thrombocytopenia (HIT).
  
  
  RESULTS
  HIT is a life-threatening thrombotic disease in which IgG antibodies against the heparin-platelet factor 4 complex activate platelets via FcγRIIA. We reported previously differential expression of TULA-2 in human population was linked to FcγRIIA responsiveness. In this study, we investigated the role of TULA-2, a protein phosphatase, in the FcγRIIA pathway and HIT pathogenesis by crossing TULA-2-/-mice with transgenic FcγRIIA+/+mice. Ablation of TULA-2 resulted in hyperphosphorylation of spleen tyrosine kinase, linker for the activation of T cells, and phospholipase Cγ2 in platelets via FcγRIIA activation. Platelet integrin activation, granule secretion, phosphatidylserine exposure, and aggregation were also enhanced in TULA-2-/-murine platelets. Compared with wild-type mice, TULA-2-/-mice showed aggravated antibody-mediated thrombocytopenia, augmented thrombin generation, and shortened tail bleeding time. In contrast, there was no significant difference between TULA-2-/-and TULA-2+/+platelets in platelet spreading and clot retraction. Of note, heterozygous TULA-2+/-mice, whose platelets contained 50% as much protein as the TULA-2+/+platelets, showed significantly increased platelet reactivity and more severe thrombocytopenia in vivo compared with TULA-2+/+mice.
  
  
  CONCLUSIONS
  Together, the data demonstrate that not only the absence of TULA-2 but also the relative level of TULA-2 expression modulates FcγRIIA-mediated platelet reactivity and HIT in vivo. TULA-2 expression could be a valuable marker for HIT and inhibiting TULA-2 may serve as a potential therapy to reverse the bleeding adverse effect of anticoagulants.
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA (Y.Z., S.A., S.R., L.C.E., P.F.B., S.E.M.); and Department of Physiology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA (C.A.D., A.Y.T., S.P.K.).
authors.forename: Yuhang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA (Y.Z., S.A., S.R., L.C.E., P.F.B., S.E.M.); and Department of Physiology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA (C.A.D., A.Y.T., S.P.K.).
authors.forename: Shaji
authors.initials: S
authors.lastname: Abraham
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA (Y.Z., S.A., S.R., L.C.E., P.F.B., S.E.M.); and Department of Physiology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA (C.A.D., A.Y.T., S.P.K.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: Renna
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA (Y.Z., S.A., S.R., L.C.E., P.F.B., S.E.M.); and Department of Physiology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA (C.A.D., A.Y.T., S.P.K.).
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Edelstein
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA (Y.Z., S.A., S.R., L.C.E., P.F.B., S.E.M.); and Department of Physiology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA (C.A.D., A.Y.T., S.P.K.).
authors.forename: Carol A
authors.initials: CA
authors.lastname: Dangelmaier
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA (Y.Z., S.A., S.R., L.C.E., P.F.B., S.E.M.); and Department of Physiology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA (C.A.D., A.Y.T., S.P.K.).
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Tsygankov
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA (Y.Z., S.A., S.R., L.C.E., P.F.B., S.E.M.); and Department of Physiology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA (C.A.D., A.Y.T., S.P.K.).
authors.forename: Satya P
authors.initials: SP
authors.lastname: Kunapuli
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA (Y.Z., S.A., S.R., L.C.E., P.F.B., S.E.M.); and Department of Physiology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA (C.A.D., A.Y.T., S.P.K.).
authors.forename: Paul F
authors.initials: PF
authors.lastname: Bray
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA (Y.Z., S.A., S.R., L.C.E., P.F.B., S.E.M.); and Department of Physiology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA (C.A.D., A.Y.T., S.P.K.). steven.mckenzie@jefferson.edu.
authors.forename: Steven E
authors.initials: SE
authors.lastname: McKenzie
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D004195:Disease Models, Animal; D005838:Genotype; D006487:Hemostasis; D006493:Heparin; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D051966:Phospholipase C gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010974:Platelet Aggregation; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C445323:FCGR2A protein, human; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D017452:Receptors, IgG; D006493:Heparin; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D017027:Protein Tyrosine Phosphatases; C553497:TULA-2 protein, mouse; D051966:Phospholipase C gamma; D013917:Thrombin
keywords: hematology; hemostasis; heparin; thrombocytopenia; thrombosis