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Bimp1, a MAGUK Family Member Linking Protein Kinase C Activation to Bcl10-mediated NF-κB Induction*

Open AccessPublished:August 01, 2001DOI:https://doi.org/10.1074/jbc.M103824200
      Bcl10 and MALT1, products of distinct chromosomal translocations in mucosa-associated lymphoid tissue lymphoma, cooperate in activating NF-κB. Mice lacking Bcl10 demonstrate severe immunodeficiency associated with failure of lymphocytes to activate nuclear factor κB (NF-κB) in response to antigen receptor stimulation and protein kinase C activation. We characterize Bimp1, a new signaling protein that binds Bcl10 and activates NF-κB. Bimp1-mediated NF-κB activation requires Bcl10 and IκB kinases, indicating that Bimp1 acts upstream of these mediators. Bimp1, Bcl10, and MALT1 form a ternary complex, with Bcl10 bridging the Bimp1/MALT1 interaction. A dominant negative Bimp1 mutant inhibits NF-κB activation by anti-CD3 ligation, phorbol ester, and protein kinase C expression. These results suggest that Bimp1 links surface receptor stimulation and protein kinase C activation to Bcl10/MALT1, thus leading to NF-κB induction.
      MALT
      mucosa-associated lymphoid tissue
      NF-κB
      nuclear factor κB
      CARD
      caspase recruitment domain
      IκB
      inhibitor of NF-κB
      IKK
      IκB kinase
      TNF
      tumor necrosis factor
      MEF
      mouse embryonic fibroblast
      PKC
      protein kinase C
      PMA
      phorbol myristylacetate
      FKBP
      FK506-binding protein
      TLR
      Toll-like receptor
      SH
      Src homology
      PDZ
      Z0–1 homologous
      GUK
      guanylate kinase
      EST
      expressed sequence tag
      HA
      hemagglutinin
      PAGE
      polyacrylamide gel electrophoresis
      B-cell lymphomas of mucosa-associated lymphoid tissue (MALT)1 are the most common form of lymphoma arising in extranodal sites. MALT lymphoma most commonly occurs within the stomach where it is strongly associated with chronic Helicobacter pylori infection (
      • Zucca E.
      • Bertoni F.
      • Roggero E.
      • Cavelli F.
      ). Until recently, little has been known about the molecular events that lead to the development of MALT lymphoma. However, studies have now identified several genes that are involved in recurrent chromosomal translocations in MALT lymphoma. The t(1;14)(p22:q32) results in the placement of the entire coding region of the Bcl10 gene adjacent to the strong immunoglobulin heavy chain locus transcriptional enhancer, leading to deregulated overexpression of Bcl10 (
      • Willis T.G.
      • Jadayel D.M.
      • Du M.-Q.
      • Peng H.
      • Perry A.R.
      • Abdul-Rauf M.
      • Price H.
      • Karran L.
      • Majekodunmi L.
      • Wlodarska I.
      • Pan L.
      • Crook T.
      • Hamoudi R.
      • Isaacson P.G.
      • Dyer M.J.S.
      ,
      • Zhang Q.
      • Siebert R.
      • Yan M.
      • Hinzmann B.
      • Cui X.
      • Xue L.
      • Rakestraw K.M.
      • Naeve C.W.
      • Beckmann G.
      • Weisenburger D.D.
      • Sanger W.G.
      • Nowatny H.
      • Vesely M.
      • Callet-Bauchu E.
      • Salles G.
      • Dixit V.M.
      • Rosenthal A.
      • Schlegelberger B.
      • Morris S.W.
      ). A second recurrent chromosomal translocation, t(11;18)(q21;q21), is seen in up to 50% of MALT lymphomas. This translocation results in the creation of a fusion gene that encodes a chimeric protein consisting of the N-terminal portion of the inhibitor of apoptosis, c-IAP-2 (also known as AP12) linked to the C terminus of a novel protein, MALT1 (
      • Akagi T.
      • Motegi M.
      • Tamura A.
      • Suzuki R.
      • Hosokawa Y.
      • Suzuki H.
      • Ota H.
      • Nakamura S.
      • Morishima Y.
      • Taniwaki M.
      • Seto M.
      ,
      • Dierlamm J.
      • Baens M.
      • Wlodarska I.
      • Stefanova-Ouzounova M.
      • Hernandez J.M.
      • Hossfeld D.K.
      • DeWolf-Peeters C.
      • Hagameijer A.
      • Vanden Berghe H.
      • Marynen P.
      ,
      • Morgan J.A.
      • Yin Y.
      • Borowsky A.D.
      • Kuo F.
      • Nourmand N.
      • Koontz J.I.
      • Reynolds C.
      • Soreng L.
      • Griffin C.A.
      • Graeme-Cook F.
      • Harris N.L.
      • Weisenburger D.
      • Pinkus G.
      • Fletcher J.A.
      • Sklar J.
      ).
      Bcl10 (also known as CIPER, mE10, c-CARMEN, CLAP, and c-E10) is a caspase-recruitment domain (CARD)-containing protein that activates the transcription factor NF-κB (
      • Willis T.G.
      • Jadayel D.M.
      • Du M.-Q.
      • Peng H.
      • Perry A.R.
      • Abdul-Rauf M.
      • Price H.
      • Karran L.
      • Majekodunmi L.
      • Wlodarska I.
      • Pan L.
      • Crook T.
      • Hamoudi R.
      • Isaacson P.G.
      • Dyer M.J.S.
      ,
      • Costanzo A.
      • Guiet C.
      • Vito P.
      ,
      • Koseki T.
      • Inohara N.
      • Chen S.
      • Carrio R.
      • Merino J.
      • Hottiger M.O.
      • Nabel G.
      • Núñez G.
      ,
      • Srinivasula S.M.
      • Ahmad M.
      • Lin J.
      • Poyet J.-L.
      • Fernandes-Alnemri T.
      • Tsichlis P.N.
      • Alnemri E.S.
      ,
      • Thome M.
      • Martinon F.
      • Hofmann K.
      • Rubio V.
      • Steiner V.
      • Schneider P.
      • Mattmann C.
      • Tschopp J.
      ,
      • Yan M.
      • Lee J.
      • Schilbach S.
      • Goddard A.
      • Dixit V.
      ). MALT1, the other target of chromosomal translocation in MALT lymphoma, is a novel protein composed of a death domain, two immunoglobulin-like domains, and a C-terminal caspase-like domain (
      • Dierlamm J.
      • Baens M.
      • Wlodarska I.
      • Stefanova-Ouzounova M.
      • Hernandez J.M.
      • Hossfeld D.K.
      • DeWolf-Peeters C.
      • Hagameijer A.
      • Vanden Berghe H.
      • Marynen P.
      ,
      • Morgan J.A.
      • Yin Y.
      • Borowsky A.D.
      • Kuo F.
      • Nourmand N.
      • Koontz J.I.
      • Reynolds C.
      • Soreng L.
      • Griffin C.A.
      • Graeme-Cook F.
      • Harris N.L.
      • Weisenburger D.
      • Pinkus G.
      • Fletcher J.A.
      • Sklar J.
      ). Recent studies have shown that MALT1 binds specifically to Bcl10 and enhances the ability of Bcl10 to activate NF-κB (
      • Uren A.G.
      • O'Rourke K.
      • Aravind L.
      • Pisabarro M.T.
      • Seshagiri S.
      • Koonin E.V.
      • Dixit V.M.
      ,
      • Lucas P.C.
      • Yonezumi M.
      • Inohara N.
      • McAllister-Lucas L.M.
      • Abazeed M.E.
      • Chen F.F.
      • Yamaoka S.
      • Seto M.
      • Núñez G.
      ). Moreover, Bcl10 mediates the oligomerization of MALT1, an event that is sufficient for NF-κB activation (
      • Lucas P.C.
      • Yonezumi M.
      • Inohara N.
      • McAllister-Lucas L.M.
      • Abazeed M.E.
      • Chen F.F.
      • Yamaoka S.
      • Seto M.
      • Núñez G.
      ). In addition, the c-IAP-2-MALT1 fusion protein resulting from the t(11;18)(q21;q21) chromosomal translocation strongly activates NF-κB (
      • Uren A.G.
      • O'Rourke K.
      • Aravind L.
      • Pisabarro M.T.
      • Seshagiri S.
      • Koonin E.V.
      • Dixit V.M.
      ,
      • Lucas P.C.
      • Yonezumi M.
      • Inohara N.
      • McAllister-Lucas L.M.
      • Abazeed M.E.
      • Chen F.F.
      • Yamaoka S.
      • Seto M.
      • Núñez G.
      ). These observations suggest that MALT1 functions as a downstream effector in a Bcl10-MALT1 complex, and that Bcl10 and MALT1, although independent targets of chromosomal translocation, act in a common NF-κB signaling pathway to promote MALT lymphoma.
      Analysis of mutant mice lacking Bcl10 have shown that this protein plays a critical role in lymphoid activation and proliferation (
      • Ruland J.
      • Duncan G.S.
      • Elia A.
      • del Barco Barrantes I.
      • Nguyen L.
      • Plyte S.
      • Millar D.G.
      • Bouchard D.
      • Wakeham A.
      • Ohashi P.S.
      • Mak T.W.
      ). In addition, Bcl10 is important for neural development, because a significant percentage of mice deficient in Bcl10 exhibit a defect in neural tube closure (
      • Ruland J.
      • Duncan G.S.
      • Elia A.
      • del Barco Barrantes I.
      • Nguyen L.
      • Plyte S.
      • Millar D.G.
      • Bouchard D.
      • Wakeham A.
      • Ohashi P.S.
      • Mak T.W.
      ). Bcl10 −/− lymphocytes fail to activate NF-κB in response to CD3, CD3/CD28, and IgM ligation, indicating that Bcl10 is a signal transducer between lymphoid antigen receptors and NF-κB (
      • Ruland J.
      • Duncan G.S.
      • Elia A.
      • del Barco Barrantes I.
      • Nguyen L.
      • Plyte S.
      • Millar D.G.
      • Bouchard D.
      • Wakeham A.
      • Ohashi P.S.
      • Mak T.W.
      ). One class of signaling molecules that has been implicated in mediating both T-cell receptor and B-cell receptor signaling is the family of protein kinase C (PKC) enzymes. Mounting evidence suggests that the PMA-activated isoforms such as PKCθ and PKCβ are important in CD3/CD28 and IgM receptor-mediated NF-κB induction, respectively (
      • Leitges M.
      • Schmedt C.
      • Guinamard R.
      • Davoust J.
      • Schaal S.
      • Stabel S.
      • Tarakhovsky A.
      ,
      • Coudronniere N.
      • Villalba M.
      • Englund N.
      • Altman A.
      ,
      • Lin X.
      • O'Mahony A.
      • Mu Y.
      • Geleziunas R.
      • Greene W.C.
      ,
      • Sun Z.
      • Arendt C.W.
      • Ellmeier W.
      • Schaeffer E.M.
      • Sunshine M.J.
      • Gandhi L
      • Annes J.
      • Schwartzberg P.L.
      • Littman D.R.
      ). Bcl10 −/− lymphoid cells retain normal Ca2+ mobilization but are defective in NF-κB stimulation induced by PMA/Ca2+ ionophore, suggesting that Bcl10 acts downstream of PKC in the antigen receptor-mediated signaling pathway (
      • Ruland J.
      • Duncan G.S.
      • Elia A.
      • del Barco Barrantes I.
      • Nguyen L.
      • Plyte S.
      • Millar D.G.
      • Bouchard D.
      • Wakeham A.
      • Ohashi P.S.
      • Mak T.W.
      ).
      Until now, proteins operating upstream of the Bcl10-MALT1 signaling complex have not been definitively identified. MALT1, a proposed downstream effector of Bcl10, does not contain a CARD, and therefore cannot participate in a CARD/CARD interaction with Bcl10. Recently, the protein CARD9 was identified as a CARD-containing protein that interacts selectively with the CARD of Bcl10, but the physiological significance of this binding has not yet been explored (
      • Bertin J.
      • Guo Y.
      • Wang L.
      • Srinivasula S.M.
      • Jacobson M.D.
      • Poyet J.-L.
      • Merriam S.
      • Du M.-Q.
      • Dyer M.J.S.
      • Robison K.E.
      • Distefano P.S.
      • Alnemri E.S.
      ). Furthermore, the mechanisms by which surface receptors and PKC activation are linked to Bcl10 are unknown. Here we characterize a new Bcl10-binding molecule, Bimp1 (Bcl10-interacting MAGUKprotein), a CARD-containing protein with homology to CARD9. Unlike CARD9, Bimp1 contains Src homology (SH3), Z0–1 homologous (PDZ), and guanylate kinase (GUK)-like domains. Bimp1 is a member of the MAGUK (membrane-associatedguanylate kinase) family, a class of proteins that function as molecular scaffolds in assembling multiprotein complexes at the plasma membrane (
      • Dimitratos S.D.
      • Woods D.F.
      • Stathakis D.G.
      • Bryan P.J.
      ,
      • Fanning A.S.
      • Anderson J.M.
      ). We show that Bimp1 is a component of a novel NF-κB signaling pathway that links surface receptor signaling and PKC activation to Bcl10, MALT1, and the IκB kinases (IKKs).

      DISCUSSION

      We have identified a novel protein, Bimp1, that binds Bcl10 and activates NF-κB. Bimp1 is homologous to Bimp2, another protein that also activates NF-κB in a Bcl10-dependent manner. The domain structures of Bimp1 and Bimp2 identify these proteins as members of the MAGUK family, a class of proteins that are composed of multiple discreet modules, including the SH3, PDZ, and GUK-like domains, which mediate protein-protein interaction. We propose that Bimp1 and Bimp2 represent a subfamily of MAGUK proteins that are distinguished from other subfamilies by the presence of an N-terminal CARD. As this manuscript was completed, Bertin et al. (
      • Bertin J.
      • Wang L.
      • Guo Y.
      • Jacobson M.D.
      • Poyet J.-L.
      • Srinivasula S.M.
      • Merriam S.
      • Distefano P.
      • Alnemri E.
      ) published a report identifying two CARD-containing MAGUK proteins that they named CARD11 and CARD14. CARD14 may represent the human orthologue of Bimp2. These authors showed that CARD11 and CARD14 bind to Bcl10 and activate NF-κB. However, this report does not establish whether CARD11 and CARD14 operate upstream of Bcl10, nor does it address the relationship of CARD11, CARD14, and Bcl10 to T-cell receptor triggering and PKC activation (
      • Bertin J.
      • Wang L.
      • Guo Y.
      • Jacobson M.D.
      • Poyet J.-L.
      • Srinivasula S.M.
      • Merriam S.
      • Distefano P.
      • Alnemri E.
      ).
      To our knowledge, Bimp1 is the first molecule to be definitively identified as operating upstream of Bcl10 and as linking PKC activation to Bcl10-mediated NF-κB induction. Based on our data, we propose a model for a Bimp-mediated signaling pathway leading to NF-κB activation (Fig. 6 D). In this proposed pathway, surface receptor stimulation leads to activation of PKC, and a Bimp protein functions as a critical link between PKC and Bcl10. Because the Bimp proteins are members of the MAGUK family, it is likely that Bimps function as molecular scaffolds in recruiting molecules such as plasma membrane receptors, phospholipase C, PKC, Bcl10, MALT1, and other as yet unidentified molecules to a large signaling complex, thereby holding together the signaling components that allow NF-κB activation to occur (Fig. 6 D). The Bimps may, like many MAGUK proteins, anchor to the cytoplasmic tail of surface receptors through PDZ domain interaction (
      • Dimitratos S.D.
      • Woods D.F.
      • Stathakis D.G.
      • Bryan P.J.
      ). Our data suggest that Bimp1 operates immediately upstream of Bcl10 with the CARD/CARD interaction between Bcl10 and Bimp1 being essential for NF-κB signaling. Bimp1, Bcl10, and MALT1 can form a ternary complex whereby Bcl10 links Bimp1 to MALT1. The formation of this multiprotein complex has functional significance because Bimp1, Bcl10, and MALT1 can cooperate to activate NF-κB. Recent studies have shown that MALT1 binds to Bcl10 through its immunoglobulin domains (
      • Uren A.G.
      • O'Rourke K.
      • Aravind L.
      • Pisabarro M.T.
      • Seshagiri S.
      • Koonin E.V.
      • Dixit V.M.
      ,
      • Lucas P.C.
      • Yonezumi M.
      • Inohara N.
      • McAllister-Lucas L.M.
      • Abazeed M.E.
      • Chen F.F.
      • Yamaoka S.
      • Seto M.
      • Núñez G.
      ). Furthermore, Bcl10 mediates the oligomerization of MALT1, an event that is sufficient for NF-κB activation, thus suggesting that MALT1 is a downstream effector of Bcl10 (
      • Lucas P.C.
      • Yonezumi M.
      • Inohara N.
      • McAllister-Lucas L.M.
      • Abazeed M.E.
      • Chen F.F.
      • Yamaoka S.
      • Seto M.
      • Núñez G.
      ). It is not known whether MALT1 is the only downstream effector of Bcl10 or whether other molecules also function downstream of Bcl10. Bimp1/Bcl10-mediated activation of NF-κB occurs through a mechanism that requires the regulatory subunit IKKγ and the kinase subunits IKKα or IKKβ of the IKK complex. The molecular events that link oligomerization and activation of the MALT1 caspase-like domain to activation of the IKK complex remain unknown.
      Recent knockout studies revealed that the Bcl10-mediated NF-κB activation pathway plays an essential role in antigen receptor signaling in B- and T-cells (
      • Ruland J.
      • Duncan G.S.
      • Elia A.
      • del Barco Barrantes I.
      • Nguyen L.
      • Plyte S.
      • Millar D.G.
      • Bouchard D.
      • Wakeham A.
      • Ohashi P.S.
      • Mak T.W.
      ). In addition, the diacylglycerol/PMA-sensitive PKC isoforms have also been implicated as critical components of NF-κB signaling in lymphoid cells (
      • Leitges M.
      • Schmedt C.
      • Guinamard R.
      • Davoust J.
      • Schaal S.
      • Stabel S.
      • Tarakhovsky A.
      ,
      • Coudronniere N.
      • Villalba M.
      • Englund N.
      • Altman A.
      ,
      • Lin X.
      • O'Mahony A.
      • Mu Y.
      • Geleziunas R.
      • Greene W.C.
      ,
      • Sun Z.
      • Arendt C.W.
      • Ellmeier W.
      • Schaeffer E.M.
      • Sunshine M.J.
      • Gandhi L
      • Annes J.
      • Schwartzberg P.L.
      • Littman D.R.
      ). For example, antigen receptor stimulation in T-cells activates PKCθ, a step that is required for NF-κB induction (
      • Sun Z.
      • Arendt C.W.
      • Ellmeier W.
      • Schaeffer E.M.
      • Sunshine M.J.
      • Gandhi L
      • Annes J.
      • Schwartzberg P.L.
      • Littman D.R.
      ). Likewise, PKCβ has been shown to be essential for antigen receptor signaling in B-cells (
      • Leitges M.
      • Schmedt C.
      • Guinamard R.
      • Davoust J.
      • Schaal S.
      • Stabel S.
      • Tarakhovsky A.
      ). We have now identified a molecule, Bimp1, which appears to link PKC activation to the Bcl10-dependent pathway of NF-κB induction. Importantly, the role of Bimp1 in lymphocytes is specifically demonstrated by our studies of CD3 signaling in T-cell hybridomas. In these cells, activation of NF-κB by anti-CD3 is completely blocked by a dominant negative mutant of Bimp1. The notion that PKC, Bimp1, and Bcl10 participate in a common NF-κB signaling pathway is supported by the fact that mice deficient in PKCθ and PKCβ demonstrate defects in lymphoid activation that are similar to those observed in mice lacking Bcl10 (
      • Leitges M.
      • Schmedt C.
      • Guinamard R.
      • Davoust J.
      • Schaal S.
      • Stabel S.
      • Tarakhovsky A.
      ,
      • Sun Z.
      • Arendt C.W.
      • Ellmeier W.
      • Schaeffer E.M.
      • Sunshine M.J.
      • Gandhi L
      • Annes J.
      • Schwartzberg P.L.
      • Littman D.R.
      ).
      Although our results implicate Bimp1 in linking T-cell receptor stimulation and PKC activation to Bcl10, it is possible that Bimp1 and Bimp2 may also be involved in PKC-dependent NF-κB signaling pathways in a wide array of other physiologic systems including the developing neural system. Embryos from mice lacking Bcl10 as well as embryos lacking both IKKα and IKKβ exhibit defects in neural tube closure associated with enhanced apoptosis in the hindbrain neuroepithelium (
      • Ruland J.
      • Duncan G.S.
      • Elia A.
      • del Barco Barrantes I.
      • Nguyen L.
      • Plyte S.
      • Millar D.G.
      • Bouchard D.
      • Wakeham A.
      • Ohashi P.S.
      • Mak T.W.
      ,
      • Li Q.
      • Estepa G.
      • Memet S.
      • Israel A.
      • Verma I.M.
      ). These observations suggest that Bcl10-mediated NF-κB activation acts in a survival pathway to protect developing neurons. It will be important to determine whether PKC and Bimp proteins act upstream of Bcl10 in this neuronal survival pathway.
      The importance of Bimps in linking PKC activation to NF-κB signaling may extend to cellular processes other than lymphocyte activation and central nervous development. Recent studies suggest that PKC isoforms other than PKCθ and PKCβ may mediate the induction of NF-κB in a variety of physiologic systems. For example, PKCε activation is a critical step in the induction of NF-κB by platelet-derived growth factor (
      • Tojima Y.
      • Fujimoto A.
      • Delhase M.
      • Chen Y.
      • Hatakeyama S.
      • Nakayama K.
      • Kaneko Y.
      • Nimura Y.
      • Motoyama N.
      • Ikeda K.
      • Karin M.
      • Nakanishi M.
      ). Also, the induction of NF-κB that occurs in protective ischemic preconditioning in cardiomyocytes is mediating by PKCε (
      • Li R.C.
      • Ping P.
      • Zhang J.
      • Wead W.B.
      • Cao X.
      • Gao J.
      • Zheng Y.
      • Huang S.
      • Han J.
      • Bolli R.
      ). PKCα has been implicated as an upstream activator of NF-κB in both human osteosarcoma and lung epithelial cell lines (
      • Chen C.C.
      • Sun Y.T.
      • Chen J.J.
      • Chiu K.T.
      ,
      • Vertegaal A.C.O.
      • Kuiperij H.B.
      • Yamaoka S.
      • Courtois G.
      • van der Eb A.J.
      • Zantema A.
      ). The finding that dominant negative Bimp1 inhibits NF-κB activation induced by both PKCα and PKCε suggests that Bimp1 may be involved in linking multiple classical and novel PKC isoforms to NF-κB activation in a variety of cells. These events could be mediated by either Bimp1 and/or Bimp2, because these CARD/MAGUK proteins are highly homologous and are likely to participate in similar signaling pathways. Future studies will be aimed at exploring the potential role of the PKC/Bimp/Bcl10-MALT1 pathway in a variety of physiologic systems, identifying the upstream signals that trigger activation of PKC and characterizing the mechanism(s) by which PKC activation is linked to Bimp/Bcl10-MALT1 proteins in this novel NF-κB signaling pathway.

      Acknowledgments

      We thank J. Moscat, R. Medzhitov, F. Mercurio, H. Ichijo, and A. Kimchi for providing expression plasmids, M. Kubo for T-cell hybridoma 68-41 cells, Victor Rivera (Ariad Pharmaceuticals) for FKBP plasmids and the dimerization agent AP151, and H. C. Chang for anti-CD3 antibody and many helpful discussions.

      REFERENCES

        • Zucca E.
        • Bertoni F.
        • Roggero E.
        • Cavelli F.
        Blood. 2000; 96: 410-419
        • Willis T.G.
        • Jadayel D.M.
        • Du M.-Q.
        • Peng H.
        • Perry A.R.
        • Abdul-Rauf M.
        • Price H.
        • Karran L.
        • Majekodunmi L.
        • Wlodarska I.
        • Pan L.
        • Crook T.
        • Hamoudi R.
        • Isaacson P.G.
        • Dyer M.J.S.
        Cell. 1999; 96: 35-45
        • Zhang Q.
        • Siebert R.
        • Yan M.
        • Hinzmann B.
        • Cui X.
        • Xue L.
        • Rakestraw K.M.
        • Naeve C.W.
        • Beckmann G.
        • Weisenburger D.D.
        • Sanger W.G.
        • Nowatny H.
        • Vesely M.
        • Callet-Bauchu E.
        • Salles G.
        • Dixit V.M.
        • Rosenthal A.
        • Schlegelberger B.
        • Morris S.W.
        Nat. Genet. 1999; 22: 63-68
        • Akagi T.
        • Motegi M.
        • Tamura A.
        • Suzuki R.
        • Hosokawa Y.
        • Suzuki H.
        • Ota H.
        • Nakamura S.
        • Morishima Y.
        • Taniwaki M.
        • Seto M.
        Oncogene. 1999; 18: 5785-5794
        • Dierlamm J.
        • Baens M.
        • Wlodarska I.
        • Stefanova-Ouzounova M.
        • Hernandez J.M.
        • Hossfeld D.K.
        • DeWolf-Peeters C.
        • Hagameijer A.
        • Vanden Berghe H.
        • Marynen P.
        Blood. 1999; 93: 3601-3609
        • Morgan J.A.
        • Yin Y.
        • Borowsky A.D.
        • Kuo F.
        • Nourmand N.
        • Koontz J.I.
        • Reynolds C.
        • Soreng L.
        • Griffin C.A.
        • Graeme-Cook F.
        • Harris N.L.
        • Weisenburger D.
        • Pinkus G.
        • Fletcher J.A.
        • Sklar J.
        Cancer Res. 1999; 59: 6205-6213
        • Costanzo A.
        • Guiet C.
        • Vito P.
        J. Biol. Chem. 1999; 274: 20127-20132
        • Koseki T.
        • Inohara N.
        • Chen S.
        • Carrio R.
        • Merino J.
        • Hottiger M.O.
        • Nabel G.
        • Núñez G.
        J. Biol. Chem. 1999; 274: 9955-9961
        • Srinivasula S.M.
        • Ahmad M.
        • Lin J.
        • Poyet J.-L.
        • Fernandes-Alnemri T.
        • Tsichlis P.N.
        • Alnemri E.S.
        J. Biol. Chem. 1999; 274: 17946-17954
        • Thome M.
        • Martinon F.
        • Hofmann K.
        • Rubio V.
        • Steiner V.
        • Schneider P.
        • Mattmann C.
        • Tschopp J.
        J. Biol. Chem. 1999; 274: 9962-9968
        • Yan M.
        • Lee J.
        • Schilbach S.
        • Goddard A.
        • Dixit V.
        J. Biol. Chem. 1999; 274: 10287-10292
        • Uren A.G.
        • O'Rourke K.
        • Aravind L.
        • Pisabarro M.T.
        • Seshagiri S.
        • Koonin E.V.
        • Dixit V.M.
        Mol. Cell. 2000; 6: 961-967
        • Lucas P.C.
        • Yonezumi M.
        • Inohara N.
        • McAllister-Lucas L.M.
        • Abazeed M.E.
        • Chen F.F.
        • Yamaoka S.
        • Seto M.
        • Núñez G.
        J. Biol. Chem. 2001; 276: 19012-19019
        • Ruland J.
        • Duncan G.S.
        • Elia A.
        • del Barco Barrantes I.
        • Nguyen L.
        • Plyte S.
        • Millar D.G.
        • Bouchard D.
        • Wakeham A.
        • Ohashi P.S.
        • Mak T.W.
        Cell. 2001; 104: 33-42
        • Leitges M.
        • Schmedt C.
        • Guinamard R.
        • Davoust J.
        • Schaal S.
        • Stabel S.
        • Tarakhovsky A.
        Science. 1996; 9: 788-791
        • Coudronniere N.
        • Villalba M.
        • Englund N.
        • Altman A.
        Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3394-3399
        • Lin X.
        • O'Mahony A.
        • Mu Y.
        • Geleziunas R.
        • Greene W.C.
        Mol. Cell. Biol. 2000; 20: 2933-2940
        • Sun Z.
        • Arendt C.W.
        • Ellmeier W.
        • Schaeffer E.M.
        • Sunshine M.J.
        • Gandhi L
        • Annes J.
        • Schwartzberg P.L.
        • Littman D.R.
        Nature. 2000; 404: 402-407
        • Bertin J.
        • Guo Y.
        • Wang L.
        • Srinivasula S.M.
        • Jacobson M.D.
        • Poyet J.-L.
        • Merriam S.
        • Du M.-Q.
        • Dyer M.J.S.
        • Robison K.E.
        • Distefano P.S.
        • Alnemri E.S.
        J. Biol. Chem. 2000; 275: 41082-41086
        • Dimitratos S.D.
        • Woods D.F.
        • Stathakis D.G.
        • Bryan P.J.
        BioEssays. 1999; 21: 912-921
        • Fanning A.S.
        • Anderson J.M.
        Curr. Opin. Cell Biol. 1999; 11: 432-439
        • Inohara N.
        • Koseki T.
        • del Peso L.
        • Hu Y.
        • Yee C.
        • Chen S.
        • Carrio R.
        • Merino J.
        • Liu D.
        • Ni J.
        • Núñez G.
        J. Biol. Chem. 1999; 274: 14560-14567
        • Inohara N.
        • Koseki T.
        • Lin J.
        • del Peso L.
        • Lucas P.C.
        • Chen F.F.
        • Ogura Y.
        • Núñez G.
        J. Biol. Chem. 2000; 275: 27823-27831
        • Lallena M.-J.
        • Diz-Meco M.T.
        • Bren G.
        • Paya C.V.
        • Moscat J.
        Mol. Cell. Biol. 1999; 19: 2180-2188
        • Medzhitov R.
        • Preston-Hurlburt P.
        • Kopp E.
        • Stadlen A.
        • Chen C.
        • Gosh S.
        • Janeway C.A.
        Mol. Cell. 1998; 2: 253-258
        • Perkins N.D.
        • Felzien L.K.
        • Betts J.C.
        • Leung K.
        • Beach D.H.
        • Nabel G.J.
        Science. 1997; 275: 523-527
        • Shimada T.
        • Kawai T.
        • Takeda K.
        • Matsumoto M.
        • Inoue J.
        • Tatsumi Y.
        • Kanamaru A.
        • Akira S.
        Int. Immunol. 1999; 11: 1357-1362
        • Li Q.
        • Estepa G.
        • Memet S.
        • Israel A.
        • Verma I.M.
        Genes Dev. 2000; 14: 1729-1733
        • Oltvai Z.N.
        • Korsmeyer S.J.
        Cell. 1994; 79: 189-192
        • Lupas A.
        Trends Biochem. Sci. 1996; 21: 375-382
        • Karin M.
        • Ben-Neriah Y.
        Annu. Rev. Immunol. 2000; 18: 621-663
        • Yamaoka S.
        • Courtois G.
        • Bessia C.
        • Whiteside S.T.
        • Weil R.
        • Agou F.
        • Kirk H.E.
        • Kay R.J.
        • Israel A.
        Cell. 1998; 93: 1231-1240
        • Hofmann K.
        • Bucher P.
        Trends Biochem. Sci. 1997; 22: 155-156
        • Medzhitov R.
        • Preston-Hurlburt P.
        • Janeway Jr., C.A.
        Nature. 1997; 388: 394-397
        • Tokoyoda K.
        • Takemoto Y.
        • Nakayama T.
        • Arai T.
        • Kubo M.
        J. Biol. Chem. 2000; 275: 11728-11734
        • Cohen O.
        • Feinstein E.
        • Kimchi A.
        EMBO J. 1997; 16: 998-1008
        • Bertin J.
        • Wang L.
        • Guo Y.
        • Jacobson M.D.
        • Poyet J.-L.
        • Srinivasula S.M.
        • Merriam S.
        • Distefano P.
        • Alnemri E.
        J. Biol. Chem. 2001; 276: 11877-11882
        • Tojima Y.
        • Fujimoto A.
        • Delhase M.
        • Chen Y.
        • Hatakeyama S.
        • Nakayama K.
        • Kaneko Y.
        • Nimura Y.
        • Motoyama N.
        • Ikeda K.
        • Karin M.
        • Nakanishi M.
        Nature. 2000; 404: 778-782
        • Li R.C.
        • Ping P.
        • Zhang J.
        • Wead W.B.
        • Cao X.
        • Gao J.
        • Zheng Y.
        • Huang S.
        • Han J.
        • Bolli R.
        Am. J. Physiol. 2000; 279: H1679-H1689
        • Chen C.C.
        • Sun Y.T.
        • Chen J.J.
        • Chiu K.T.
        J. Immunol. 2000; 165: 2719-2728
        • Vertegaal A.C.O.
        • Kuiperij H.B.
        • Yamaoka S.
        • Courtois G.
        • van der Eb A.J.
        • Zantema A.
        Cell. Signal. 2000; 12: 759-768
        • Qin H.
        • Srinivasula S.M.
        • Wu G.
        • Fernandes-Alnemri T.
        • Alnemri E.S.
        • Shi Y.
        Nature. 1999; 399: 549-557