TULA-2 (T-Cell Ubiquitin Ligand-2) Inhibits the Platelet Fc Receptor for IgG IIA (FcγRIIA) Signaling Pathway and Heparin-Induced Thrombocytopenia in Mice (original) (raw)
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TULA-2 Deficiency Enhances Platelet Functional Responses to CLEC-2 Agonists
TH Open
Platelet activation is essential for hemostasis. Central to platelet activation are the signals transmitted through surface receptors such as glycoprotein VI, the protease-activated receptors, and C-type lectin-like receptor 2 (CLEC-2). CLEC-2 is a HemITAM (hem-immunoreceptor tyrosine activation motif)-bearing receptor that binds podoplanin and signals through spleen tyrosine kinase (Syk). T-cell ubiquitin ligand-2 (TULA-2) is a protein tyrosine phosphatase that is highly expressed in platelets and targets phosphorylated Y352 of Syk. We wanted to determine whether TULA-2 regulates Syk phosphorylation and activity downstream of CLEC-2. To that end, we used TULA-2 knockout mice and wild-type (WT) littermate controls. We found that TULA-2 deficiency enhances the aggregation and secretion response following stimulation with an excitatory CLEC-2 antibody or the CLEC-2 agonist rhodocytin. Consistently, Syk phosphorylation of Y346 is enhanced, as well as phosphorylation of the downstream s...
Increased expression of platelet IgG Fc receptors in immune heparin-induced thrombocytopenia
Blood, 1993
Our previous finding that heparin-dependent antibodies in heparin-induced thrombocytopenia (HIT) bind to platelets via platelet IgG Fc receptors (FcRs) prompted this study. Platelet FcRs in 16 patients with HIT, 23 control patients, and 42 normal subjects were studied. Patients with HIT had substantially increased platelet FcRs during the acute illness. Those who suffered serious thrombotic complications or died shortly after diagnosis had significantly more FcRs per platelet than those with milder disease. Consistent with their increased FcRs, platelets of patients with HIT showed increased aggregation reactivity to aggregated IgG and heparin-dependent antibodies. Platelet FcRs in patients with HIT remained elevated for 1 to 3 months after the acute illness then stabilized to a mean value not significantly different from either control group. The increased expression of FcRs on HIT platelets and their increased reactivity to heparin-dependent antibodies may contribute to the pathog...
Blood, 2010
T-cell ubiquitin ligand-2 (TULA-2) is a recently discovered histidine tyrosine phosphatase thought to be ubiquitously expressed. In this work, we have investigated whether TULA-2 has a key role in platelet glycoprotein VI (GPVI) signaling. This study indicates that TULA-2 is expressed in human and murine platelets and is able to associate with Syk and dephosphorylate it. Ablation of TULA-2 resulted in hyperphosphorylation of Syk and its downstream effector phospholipase C-γ2 as well as enhanced GPVI-mediated platelet functional responses. In addition, shorter bleeding times and a prothrombotic phenotype were observed in mice lacking TULA-2. We therefore propose that TULA-2 is the primary tyrosine phosphatase mediating the dephosphorylation of Syk and thus functions as a negative regulator of GPVI signaling in platelets.
TULA-Family Regulators of Platelet Activation
International Journal of Molecular Sciences
The two members of the UBASH3/TULA/STS-protein family have been shown to critically regulate cellular processes in multiple biological systems. The regulatory function of TULA-2 (also known as UBASH3B or STS-1) in platelets is one of the best examples of the involvement of UBASH3/TULA/STS proteins in cellular regulation. TULA-2 negatively regulates platelet signaling mediated by ITAM- and hemITAM-containing membrane receptors that are dependent on the protein tyrosine kinase Syk, which currently represents the best-known dephosphorylation target of TULA-2. The biological responses of platelets to collagen and other physiological agonists are significantly downregulated as a result. The protein structure, enzymatic activity and regulatory functions of UBASH3/TULA/STS proteins in the context of platelet responses and their regulation are discussed in this review.
Functional expression of IgA receptor FcαRI on human platelets
Journal of Leukocyte Biology, 2008
FcαRI (CD89) is a human IgA FcR expressed on cells of myeloid lineage such as neutrophils, monocytes, tissue macrophages, eosinophils, and subpopulations of dendritic cells. FcαRI mediates cell activation through Src family kinases and downstream tyrosine-based phosphorylation pathways. However, the role of IgA and the expression and role of its cognate receptor FcαRI (CD89) in platelet activation are undefined. In the current study, we demonstrate that human platelets express FcαRI mRNAs and proteins. Furthermore, we show that the platelet FcαRI is associated with the FcR γ-chain, and cross-linking of FcαRI leads to Syk phosphorylation. Clustering of FcαRI induces pre-mRNA splicing and protein production of tissue factor and IL-1β, suggesting novel roles for human platelet FcαRI and serum IgA in thrombosis and inflammation.
Functional expression of IgA receptor Fc RI on human platelets
Journal of Leukocyte Biology, 2008
Fc␣RI (CD89) is a human IgA FcR expressed on cells of myeloid lineage such as neutrophils, monocytes, tissue macrophages, eosinophils, and subpopulations of dendritic cells. Fc␣RI mediates cell activation through Src family kinases and downstream tyrosine-based phosphorylation pathways. However, the role of IgA and the expression and role of its cognate receptor Fc␣RI (CD89) in platelet activation are undefined. In the current study, we demonstrate that human platelets express Fc␣RI mRNAs and proteins. Furthermore, we show that the platelet Fc␣RI is associated with the FcR ␥-chain, and cross-linking of Fc␣RI leads to Syk phosphorylation. Clustering of Fc␣RI induces pre-mRNA splicing and protein production of tissue factor and IL-1, suggesting novel roles for human platelet Fc␣RI and serum IgA in thrombosis and inflammation.
International Journal of Molecular Sciences, 2020
Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction characterized by thrombocytopenia and a high risk for venous or arterial thrombosis. HIT is caused by antibodies that recognize complexes of platelet factor 4 and heparin. The pathogenic mechanisms of this condition are not fully understood. In this study, we used flow cytometry, fluorimetry, and Western blot analysis to study the direct effects of pathogenic immune complexes containing platelet factor 4 on human platelets isolated by gel-filtration. HIT-like pathogenic immune complexes initially caused pronounced activation of platelets detected by an increased expression of phosphatidylserine and P-selectin. This activation was mediated either directly through the FcγRIIA receptors or indirectly via protease-activated receptor 1 (PAR1) receptors due to thrombin generated on or near the surface of activated platelets. The immune activation was later followed by the biochemical signs of cell death, such as mitochondr...
Journal of Biological Chemistry, 1999
The platelet receptor for the Fc domain of IgGs (Fc␥RIIa) triggers intracellular signaling through protein tyrosine phosphorylations leading to platelet aggregation. In this study, we focused on the adaptor protein p120 cbl (Cbl), which became tyrosine-phosphorylated after platelet activation induced by antibodies. Cbl phosphorylation was dependent on Fc receptor engagement. An association of Cbl with the p85 subunit of phosphatidylinositol 3-kinase (PI 3-K) occurred in parallel with Cbl tyrosine phosphorylation. We showed by in vitro experiments that Cbl/p85 association was mediated by the Src homology 3 domain of p85/PI 3-K and the prolinerich region of Cbl. Inhibition of PI 3-K activity by wortmannin led to the blockade of both platelet aggregation and serotonin release mediated by Fc␥RIIa engagement, whereas it only partly inhibited those induced by thrombin. Thus, PI 3-K may play a crucial role in the initiation of platelet responses after Fc␥RIIa engagement. Our results suggest that Cbl is involved in platelet signal transduction by the recruitment of PI 3-K to the Fc␥RIIa pathway, possibly by increasing PI 3-K activity.
The role of Fcγ receptors in murine autoimmune thrombocytopenia
Annals of Hematology, 2010
Immune thrombocytopenia (ITP) can become a life-threatening condition that requires immediate medical attention. The loss in platelet numbers during ITP can be induced by a variety of triggers. Anti-platelet antibodies of several isotypes and subclasses are a major cause for ITP and are a hallmark of many complex autoimmune diseases such as systemic lupus erythematosus. Mouse models have been important to understand the effector pathways involved in antibody-mediated platelet depletion. Therapeutic interventions based on these results have been proven successful in treating human ITP, thus validating the use of these model systems. One major problem that remains to be answered is which cell populations are crucial for platelet removal. Targeting these cells directly might be a novel therapeutic strategy and will also be important to understand the underlying biological mechanisms.