A novel negative regulatory function of the phosphoprotein associated with glycosphingolipid-enriched microdomains: blocking Ras activation.

Abstract:

:In primary human T cells, anergy induction results in enhanced p59Fyn activity. Because Fyn is the kinase primarily responsible for the phosphorylation of PAG (the phosphoprotein associated with glycosphingolipid-enriched microdomains), which negatively regulates Src-kinase activity by recruiting Csk (the C-terminal Src kinase) to the membrane, we investigated whether anergy induction also affects PAG. Analysis of anergic T cells revealed that PAG is hyperphosphorylated at the Csk binding site, leading to enhanced Csk recruitment and inhibitory tyrosine phosphorylation within Fyn. This together with enhanced phosphorylation of a tyrosine within the SH2 domain of Fyn leads to the formation of a hyperactive conformation, thus explaining the enhanced Fyn kinase activity. In addition, we have also identified the formation of a multiprotein complex containing PAG, Fyn, Sam68, and RasGAP in stimulated T cells. We demonstrate that PAG-Fyn overexpression is sufficient to suppress Ras activation in Jurkat T cells and show that this activity is independent of Csk binding. Thus, in addition to negatively regulating Src family kinases by recruiting Csk, PAG also negatively regulates Ras by recruiting RasGAP to the membrane. Finally, by knocking down PAG, we demonstrate both enhanced Src kinase activity and Ras activation, thereby establishing PAG as an important negative regulator of T-cell activation.

journal_name

Blood

journal_title

Blood

authors

Smida M,Posevitz-Fejfar A,Horejsi V,Schraven B,Lindquist JA

doi

10.1182/blood-2006-07-038752

subject

Has Abstract

pub_date

2007-07-15 00:00:00

pages

596-615

issue

2

eissn

0006-4971

issn

1528-0020

pii

blood-2006-07-038752

journal_volume

110

pub_type

杂志文章

相关文献

BLOOD文献大全
  • Altered development and cytokine responses of myeloid progenitors in the absence of transcription factor, interferon consensus sequence binding protein.

    abstract::Mice deficient for the transcription factor, interferon consensus sequence binding protein (ICSBP), are immunodeficient and develop disease symptoms similar to human chronic myeloid leukemia (CML). To elucidate the hematopoietic disorder of ICSBP(-/-) mice, we investigated the growth, differentiation, and leukemogenic...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Scheller M,Foerster J,Heyworth CM,Waring JF,Löhler J,Gilmore GL,Shadduck RK,Dexter TM,Horak I

    更新日期:1999-12-01 00:00:00

  • Low NAD(P)H:quinone oxidoreductase activity is associated with increased risk of leukemia with MLL translocations in infants and children.

    abstract::An inactivating polymorphism at position 609 in the NAD(P)H:quinone oxidoreductase 1 gene (NQO1 C609T) is associated with an increased risk of adult leukemia. A small British study suggested that NQO1 C609T was associated with an increased risk of infant leukemias with MLL translocations, especially infant acute lymph...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2001-12-0264

    authors: Smith MT,Wang Y,Skibola CF,Slater DJ,Lo Nigro L,Nowell PC,Lange BJ,Felix CA

    更新日期:2002-12-15 00:00:00

  • Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT.

    abstract::Natural killer (NK) cells can alter the outcome of hematopoietic cell transplantation (HCT) if donor alloreactivity targets the recipient. Since most NK cells express inhibitory killer-immunoglobulin receptors (KIRs), we hypothesized that the susceptibility of recipient cells to donor NK cell-mediated lysis is genetic...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2007-01-065383

    authors: Miller JS,Cooley S,Parham P,Farag SS,Verneris MR,McQueen KL,Guethlein LA,Trachtenberg EA,Haagenson M,Horowitz MM,Klein JP,Weisdorf DJ

    更新日期:2007-06-01 00:00:00

  • A novel serpin expressed by blood-borne microfilariae of the parasitic nematode Brugia malayi inhibits human neutrophil serine proteinases.

    abstract::Serine proteinase inhibitors (serpins) play a vital regulatory role in a wide range of biological processes, and serpins from viruses have been implicated in pathogen evasion of the host defence system. For the first time, we report a functional serpin gene from nematodes that may function in this manner. This gene, n...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Zang X,Yazdanbakhsh M,Jiang H,Kanost MR,Maizels RM

    更新日期:1999-08-15 00:00:00

  • Monoclonal antibodies bound to subunits of the integrin GPIIb-IIIa are internalized and interfere with filopodia formation and platelet aggregation.

    abstract::The monoclonal antibodies Tab and AP3 are directed, respectively, against GPIIb and GPIIIa, the subunits of the platelet fibrinogen receptor. When added together to platelets, these antibodies prevent adenosine diphosphate (ADP)-induced platelet aggregation, despite normal fibrinogen binding (Newman et al, Blood 69:66...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Isenberg WM,Bainton DF,Newman PJ

    更新日期:1990-10-15 00:00:00

  • Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991-2000).

    abstract::The reported outcome of hematopoietic stem cell transplantation (HSCT) from HLA-mismatched family members has been inconsistent. The object of this study was to evaluate the true impact of HLA-mismatch by using recent data from a homogenous population, excluding HSCT procedures that used graft manipulations, and by co...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2003-02-0430

    authors: Kanda Y,Chiba S,Hirai H,Sakamaki H,Iseki T,Kodera Y,Karasuno T,Okamoto S,Hirabayashi N,Iwato K,Maruta A,Fujimori Y,Furukawa T,Mineishi S,Matsuo K,Hamajima N,Imamura M

    更新日期:2003-08-15 00:00:00

  • Alpha4beta1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells.

    abstract::As B-cell chronic lymphocytic leukemia (B-CLL) progresses, malignant cells extravasate and infiltrate lymphoid tissues. Several molecules, including gelatinase B/MMP-9, contribute to these processes. Although mainly a secreted protease, some MMP-9 is present at the B-CLL cell surface and the function, mode of anchorin...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2007-08-109249

    authors: Redondo-Muñoz J,Ugarte-Berzal E,García-Marco JA,del Cerro MH,Van den Steen PE,Opdenakker G,Terol MJ,García-Pardo A

    更新日期:2008-07-01 00:00:00

  • Autocrine LTA signaling drives NF-κB and JAK-STAT activity and myeloid gene expression in Hodgkin lymphoma.

    abstract::Persistent NF-κB activation is a hallmark of the malignant Hodgkin/Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL). Genomic lesions, Epstein-Barr virus infection, soluble factors, and tumor-microenvironment interactions contribute to this activation. Here, in an unbiased approach to identify the cHL cel...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2018-08-871293

    authors: von Hoff L,Kärgel E,Franke V,McShane E,Schulz-Beiss KW,Patone G,Schleussner N,Kolesnichenko M,Hübner N,Daumke O,Selbach M,Akalin A,Mathas S,Scheidereit C

    更新日期:2019-03-28 00:00:00

  • Growth factors and cytokines upregulate gelatinase expression in bone marrow CD34(+) cells and their transmigration through reconstituted basement membrane.

    abstract::The mechanism(s) underlying the release of stem/progenitor cells from bone marrow into the circulation is poorly understood. We hypothesized that matrix metalloproteinases (MMPs), especially gelatinases, which are believed to participate in the proteolysis of basement membranes and in the migration of leukocytes, may ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Janowska-Wieczorek A,Marquez LA,Nabholtz JM,Cabuhat ML,Montaño J,Chang H,Rozmus J,Russell JA,Edwards DR,Turner AR

    更新日期:1999-05-15 00:00:00

  • Characterization of the retinoid binding properties of the major fusion products present in acute promyelocytic leukemia cells.

    abstract::The bcr1- and bcr3- promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) are the two major fusion proteins expressed in acute promyelocytic leukemia (APL) patients. These proteins, which are present in different lengths of PML (amino acids 1-552 and 1-394, respectively), contain most of the functional d...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Benedetti L,Levin AA,Scicchitano BM,Grignani F,Allenby G,Diverio D,Lo Coco F,Avvisati G,Ruthardt M,Adamo S,Pelicci PG,Nervi C

    更新日期:1997-08-01 00:00:00

  • DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease.

    abstract::CD4+Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft-versus-host disease (GVHD) in murine models of allogeneic hematopoietic stem cell transplantation. W...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2016-06-723783

    authors: Nishikii H,Kim BS,Yokoyama Y,Chen Y,Baker J,Pierini A,Alvarez M,Mavers M,Maas-Bauer K,Pan Y,Chiba S,Negrin RS

    更新日期:2016-12-15 00:00:00

  • The acquisition of host-derived major histocompatibility complex class II glycoproteins by human immunodeficiency virus type 1 accelerates the process of virus entry and infection in human T-lymphoid cells.

    abstract::Infection by human immunodeficiency virus type 1 (HIV-1) results in a progressive depletion of CD4+ T lymphocytes, leading to fatal immunodeficiency. The mechanisms causing the marked loss of CD4+ T lymphocytes are incompletely understood. However, several lines of evidence indicate that direct cytopathology mediated ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Cantin R,Fortin JF,Lamontagne G,Tremblay M

    更新日期:1997-08-01 00:00:00

  • How I treat chronic graft-versus-host disease.

    abstract::Allogeneic stem cell transplantation (SCT) is now a commonplace procedure. Clinicians who care for patients with hematologic malignancies and aplastic anemia are almost certain to follow up patients after SCT. This review is intended to help clinicians observe patients for probably the most important late complication...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood.v97.5.1196

    authors: Vogelsang GB

    更新日期:2001-03-01 00:00:00

  • Human monocytes and neutrophils store transforming growth factor-alpha in a subpopulation of cytoplasmic granules.

    abstract::Transforming growth factor-alpha (TGF-alpha) exerts several effects on target cells, such as neovascularization promotion and mitogenic signalling. Using immunoelectron microscopy, we show that monocytes and neutrophils, store TGF-alpha in cytoplasmic granules. In monocytes, TGF-alpha did not colocalize with component...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Calafat J,Janssen H,Ståhle-Bäckdahl M,Zuurbier AE,Knol EF,Egesten A

    更新日期:1997-08-01 00:00:00

  • Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia.

    abstract::The improved outcome of acquired aplastic anemia (AA) has revealed later complications, such as myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). We retrospectively analyzed 167 children with severe acquired AA. Eleven of 50 children treated with cyclosporin (CSA) and recombinant human granulocyte c...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Ohara A,Kojima S,Hamajima N,Tsuchida M,Imashuku S,Ohta S,Sasaki H,Okamura J,Sugita K,Kigasawa H,Kiriyama Y,Akatsuka J,Tsukimoto I

    更新日期:1997-08-01 00:00:00

  • X-linked chronic granulomatous disease: correction of NADPH oxidase defect by retrovirus-mediated expression of gp91-phox.

    abstract::Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from the inability of an individual's phagocytes to produce superoxide anions because of defective NADPH oxidase. The disease may be treated by bone marrow transplantation and as such is a candidate for somatic gene therapy. Two thirds of p...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Porter CD,Parkar MH,Levinsky RJ,Collins MK,Kinnon C

    更新日期:1993-10-01 00:00:00

  • A qualitative and quantitative analysis of the activation and inactivation of protein C in vivo in a primate model.

    abstract::A model of Protein C (PC) activation in vivo was used to investigate the complexing of activated PC (APC) with its plasma inhibitors, PC inhibitor (PCI) and alpha 1-antitrypsin (alpha 1AT). Chimpanzees were infused with a bolus of activated factor X (F.Xa) together with vesicles of phosphatidylcholine and phosphatidyl...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Hoogendoorn H,Nesheim ME,Giles AR

    更新日期:1990-06-01 00:00:00

  • Predictors of death from chronic graft-versus-host disease after bone marrow transplantation.

    abstract::Chronic graft-v-host disease (chronic GVHD) is a frequent cause of late morbidity and death after bone marrow transplantation (BMT). The actuarial survival after onset of chronic GVHD in 85 patients was 42% (95%Cl = 29%, 54%) at 10 years. Baseline characteristics present at the onset of chronic GVHD (before therapy) i...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Wingard JR,Piantadosi S,Vogelsang GB,Farmer ER,Jabs DA,Levin LS,Beschorner WE,Cahill RA,Miller DF,Harrison D

    更新日期:1989-09-01 00:00:00

  • Murine myeloproliferative disorder as a consequence of impaired collaboration between dendritic cells and CD4 T cells.

    abstract::Dendritic cells (DCs) are a key cell type in the initiation of the adaptive immune response. Recently, an additional role for DCs in suppressing myeloproliferation was discovered. Myeloproliferative disorder (MPD) was observed in murine studies with constitutive depletion of DCs, as well as in patients with congenital...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2018-05-850321

    authors: Humblet-Baron S,Barber JS,Roca CP,Lenaerts A,Koni PA,Liston A

    更新日期:2019-01-24 00:00:00

  • Extracellular histones induce erythrocyte fragility and anemia.

    abstract::Extracellular histones have been shown to play an important pathogenic role in many diseases, primarily through their cytotoxicity toward nucleated cells and their ability to promote platelet activation with resultant thrombosis and thrombocytopenia. In contrast, little is known about the effect of extracellular histo...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2017-06-790519

    authors: Kordbacheh F,O'Meara CH,Coupland LA,Lelliott PM,Parish CR

    更新日期:2017-12-28 00:00:00

  • Effects of interleukin-4 and interleukin-6 on the proliferation of CD34+ and CD34- blasts from acute myelogenous leukemia.

    abstract::We studied the effects of interleukin-4 (IL-4) and IL-6 on the growth of leukemic blasts from 40 patients with acute myelogenous leukemia (AML). Patients were selected on the basis of negativity for a series of B-cell antigens including CD10 and CD19. Twenty-one cases were CD34-positive (CD34+) (greater than 15% of bl...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Akashi K,Harada M,Shibuya T,Eto T,Takamatsu Y,Teshima T,Niho Y

    更新日期:1991-07-01 00:00:00

  • Autologous bone marrow transplantation after a long first remission for children with recurrent acute lymphoblastic leukemia.

    abstract::Fifty-one children with acute lymphoblastic leukemia (ALL) in second or subsequent remission after a first remission of at least 24 months underwent purged, autologous bone marrow transplantation (ABMT). Bone marrow was harvested in remission and purged in vitro with monoclonal antibodies specific for leukemia-associa...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Billett AL,Kornmehl E,Tarbell NJ,Weinstein HJ,Gelber RD,Ritz J,Sallan SE

    更新日期:1993-03-15 00:00:00

  • Longitudinal analysis of point mutations of the N-ras proto-oncogene in patients with myelodysplasia using archived blood smears.

    abstract::We performed a longitudinal analysis of point mutations of the N-ras proto-oncogene in patients with myelodysplasia and a follow-up of at least 2.5 years after diagnosis. Point mutations at codons 12, 13, and 61 of the N-ras oncogene were analyzed after in vitro amplification of N-ras specific sequences followed by do...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: van Kamp H,de Pijper C,Verlaan-de Vries M,Bos JL,Leeksma CH,Kerkhofs H,Willemze R,Fibbe WE,Landegent JE

    更新日期:1992-03-01 00:00:00

  • Desensitization to type I interferon in HIV-1 infection correlates with markers of immune activation and disease progression.

    abstract::Type I interferon (IFNalpha/beta) plays a complex role in HIV-1 infection and has been proposed alternately to have roles in either disease protection or progression. Although IFNalpha/beta plays crucial roles in regulating monocytes and dendritic cells, responsiveness of these cells to IFNalpha/beta in HIV-1 infectio...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2008-11-190231

    authors: Hardy GA,Sieg SF,Rodriguez B,Jiang W,Asaad R,Lederman MM,Harding CV

    更新日期:2009-05-28 00:00:00

  • Thromboprophylaxis in cancer outpatients.

    abstract::In this issue of Blood, Khorana and colleagues report a simple and practical model for the prediction of symptomatic venous thrombosis after the initiation of chemotherapy in cancer outpatients. ...

    journal_title:Blood

    pub_type: 评论,杂志文章

    doi:10.1182/blood-2008-02-137760

    authors: Doggen CJ

    更新日期:2008-05-15 00:00:00

  • Overexpression of LEF1 predicts unfavorable outcome in adult patients with B-precursor acute lymphoblastic leukemia.

    abstract::Aberrant activation of the Wnt pathway plays a pathogenetic role in various tumors and has been associated with adverse outcome in acute lymphoblastic leukemia (ALL). LEF1, a key mediator of Wnt signaling, has been linked to leukemic transformation, and recurrent mutations of LEF1 have been identified in pediatric T-A...

    journal_title:Blood

    pub_type: 临床试验,杂志文章,多中心研究

    doi:10.1182/blood-2011-04-350850

    authors: Kühnl A,Gökbuget N,Kaiser M,Schlee C,Stroux A,Burmeister T,Mochmann LH,Hoelzer D,Hofmann WK,Thiel E,Baldus CD

    更新日期:2011-12-08 00:00:00

  • Control of cell cycle progression in human natural killer cells through redox regulation of expression and phosphorylation of retinoblastoma gene product protein.

    abstract::Using thiol deprivation, we have previously shown that the response of natural killer (NK) cells to interleukin-2 (IL-2) is subject to redox regulation downstream of IL-2 binding and internalization. We have now used the IL-2-dependent cell line, NK3.3 to study redox regulation of NK cells further, and found that NK3....

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Yamauchi A,Bloom ET

    更新日期:1997-06-01 00:00:00

  • Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH).

    abstract::Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia in which venous thrombosis is the most common cause of death. Here we address the risk factors for thrombosis and the role of warfarin prophylaxis in PNH. The median follow-up of 163 PNH patients was 6 years (range, 0.2-38 years). Of the patient...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2003-01-0009

    authors: Hall C,Richards S,Hillmen P

    更新日期:2003-11-15 00:00:00

  • Mutations of the ras proto-oncogenes in childhood monosomy 7.

    abstract::ras gene mutations are the most frequent molecular changes found in the preleukemic syndromes of adults and may play a role in initiating these diseases and in their progression to acute leukemia. However, little is known about the incidence or importance of these genetic mutations in childhood myeloproliferative stat...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Neubauer A,Shannon K,Liu E

    更新日期:1991-02-01 00:00:00

  • Arg2074Cys missense mutation in the C2 domain of factor V causing moderately severe factor V deficiency: molecular characterization by expression of the recombinant protein.

    abstract::Factor V (FV) deficiency is a rare bleeding disorder whose genetic basis has been described in a relatively small number of cases. Among a total of 12 genetic defects reported in severely or moderately severe deficient patients, 3 were missense mutations and in no case was the mechanism underlying the deficiency explo...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2002-06-1928

    authors: Duga S,Montefusco MC,Asselta R,Malcovati M,Peyvandi F,Santagostino E,Mannucci PM,Tenchini ML

    更新日期:2003-01-01 00:00:00