TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling.

Ishida, Takeshi; Tojo, Tadashi; Aoki, Tsutomu; Kobayashi, Norihiko; Ohishi, Tsukasa; Watanabe, Toshiki; Yamamoto, Tadashi; Inoue, Jun‐ichiro

doi:10.1073/pnas.93.18.9437

Cited by 321 publications

(206 citation statements)

References 53 publications

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“…TRAF2, TRAF3, TRAF5 and TRAF6 also bear an N-terminal RING finger, a zinc binding motif found in several types of intracellular proteins. [19][20][21][22][23] TNF receptor-associated factor proteins interact as homodimers or in heterodimeric complexes. For example, TRAF2 binds to TRADD, the TNFR2, LTβR, CD40 or CD30 via its C-terminal TRAF domain, probably as a heterodimeric complex with TRAF1 or TRAF5, or as a homodimer.…”

Section: Trafmentioning

confidence: 99%

Signalling by CD95 and TNF receptors: Not only life and death

Magnusson

Vaux

1999

Immunol Cell Biol

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The tumour necrosis factor receptor (TNFR)/nerve growth factor receptor (NGFR) family of molecules regulate a number of biological functions, such as growth, differentiation and apoptosis in multiple cell types. In the immune system, members of this receptor family are involved in the development of peripheral lymphoid organs, regulation of induced inflammatory responses and removal of cells at the end of an immune response.The TNFR family consists of more than 15 different molecules. Most are type I membrane proteins which resemble each other largely in their extracellular regions, which all contain 2-6 characteristic cysteine-rich domains. 1 The TNF family receptors are activated upon binding of their cognate ligands, most of which are trimers with a structure similar to TNF. Sometimes the ligands are cell bound type II membrane proteins, but several are cleaved off and appear as soluble trimers. Induction of trimers or higher order complexes of the TNF family of receptors allows their cytoplasmic domains to aggregate intracytoplasmic signalling molecules. Signalling pathways controlled by TNF receptorsThe cytoplasmic domains of the TNFR family, which are more diverse than the extracellular portions, do not have any intrinsic enzymatic activity, hence they signal by inducing aggregation of intracellular adaptor molecules (Fig. 1). Death domainsThe cytoplasmic domains of TNFR1 (p55), CD95 (Fas/ APO-1), NGFR (p75), death receptor (DR) 3, TRAIL-R1 and TRAIL-R2 all bear a motif termed a 'death domain' (DD), so-called because it is required for these receptors to transmit apoptotic signals. The DD is a protein-protein interaction motif consisting of six alpha helices that allow two proteins with DD to bind to each other. Structurally the DD is related to two other homotypic interaction domains, the death effector domain (DED), and the caspase recruitment domain (CARD). 2 Death domain adaptors: TRADD, FADD, RIP and RAIDDBinding of TNF to TNFR1 induces recruitment of the DDcontaining protein TRADD to the DD of TNFR1. 3 Overexpression of TRADD alone also induces the TNF-regulated responses apoptosis and activation of the transcription factors NF-κB and Jun kinase (JNK), presumably because TRADD provides docking sites for downstream signalling proteins to the receptor complex. 4 Two of the proteins that TRADD recruits to the signalling complex also bear death domains. One of these, RIP, has an N-terminal DD and a C-terminal kinase domain. Knockout studies have shown that RIP is required for induction of NFκB by TNF. 5 The other, Fas-associated protein with death domain (FADD), has a C-terminal DD, and an N-terminal DED. The FADD is required for cell death signalling by TNFR1 and also by CD95, to which it binds directly via its death domain. [6][7][8] The DED of FADD allows it to bind to DED in the pro-domain of caspase 8.Through these interactions, ligation of TNFR1 or CD95 can result in the formation of a death-inducing signalling complex, which leads to activation of caspase 8, a cell death effector protease. Once ac...

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Section: Trafmentioning

confidence: 99%

Signalling by CD95 and TNF receptors: Not only life and death

Magnusson

Vaux

1999

Immunol Cell Biol

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“…IRAK then dissociates from the receptor complex and interacts with TRAF6, that is required for IL-1-induced NF-kB activation (Cao et al, 1996b). Two other TRAF (TNF-receptor associated factor) proteins, TRAF2 and TRAF5, have been implicated in NF-kB activation by the superfamily of TNF receptors (Aizawa et al, 1997; Duckett et al, 1997; Hsu et al, 1996aHsu et al, , 1997Ishida et al, 1996;Nakano et al, 1996;Rothe et al, 1995), indicating that IL-1 and TNF signaling converge at the level of TRAF molecules. The kinase cascade which is distal to TRAF, and is responsible for NF-kB activation, also has been elucidated.…”

Section: Egr-1 ±Modulation Of Lineage Speci®c DI Erentiation and Rolementioning

confidence: 99%

MyD genes in negative growth control

Liebermann

Hoffman

1998

Oncogene

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“…Notably, the CD40/CD154 interaction is critical for the affinity maturation of immunoglobulins (Ig), the development of long-lived plasma B cells and the clonal expansion of memory B cells [1,4,5]. In the absence of intrinsic tyrosine kinase activity, CD40 transmits its intracellular signal via recruitment of several adaptor proteins, such as JAK3 [6] and TNFR-associated factor (TRAF) proteins [5], to specific domains in the CD40 cytoplasmic tail [4,[7][8][9]. This results in the activation of members of the Src kinase family (such as Lyn and Fyn), and other protein tyrosine kinases (such as Syk and Btk) [10,11]; the activation of PI-3 kinase and phospholipase Cg2 [11] and the activation of the MAP kinases p38, JNK and ERK [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

CD40 translocation to lipid rafts: Signaling requirements and downstream biological events

et al. 2011

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CanadaCD40, a member of the TNF receptor family, is expressed on a variety of immune and nonimmune cells. Its interaction with its ligand, CD154, plays a pivotal role in humoral and cellmediated immunity. A low level of CD40 is constitutively associated within membrane lipid rafts and, upon engagement, this level is significantly enhanced. In this study, our objective is to evaluate the process of CD40/lipid raft association in terms of the signals required for its initiation and the resulting biological outcomes. Here, we show the CD40/lipid raft association to be independent of PI-3-kinase, Src family kinases and p38 MAPK pathways. Moreover, CD40 lacking its intracellular domain, which is usually required for CD40-mediated signaling, still localizes to lipid rafts upon engagement, confirming that the CD40/ lipid raft association is independent of signaling events. As to the biological outcomes of the CD40/lipid raft association, we show that disrupting lipid raft integrity selectively abolishes CD40-mediated Akt phosphorylation. In addition, replacing the transmembrane domain of CD40 with that of CD45 (a protein excluded from lipid rafts) dramatically reduced CD40-mediated Akt phosphorylation and B7.1 upregulation, while not influencing p38, ERK and JNK activation. Together, these findings clarify the requirements for CD40/lipid raft association and the signals triggered upon CD40 engagement by CD154.Keywords: CD40 . Lipid rafts . Signaling . Transmembrane domain Supporting Information available online IntroductionInteraction between the TNFR, CD40 and its ligand CD154 drives crucial steps in humoral immune responses [1][2][3]. Notably, the CD40/CD154 interaction is critical for the affinity maturation of immunoglobulins (Ig), the development of long-lived plasma B cells and the clonal expansion of memory B cells [1,4,5]. In the absence of intrinsic tyrosine kinase activity, CD40 transmits its intracellular signal via recruitment of several adaptor proteins, such as JAK3 [6] and TNFR-associated factor (TRAF) proteins [5], to specific domains in the CD40 cytoplasmic tail [4,[7][8][9]. This results in the activation of members of the Src kinase family (such as Lyn and Fyn), and other protein tyrosine kinases (such as Syk and Btk) [10,11]; the activation of PI-3 kinase and phospholipase Cg2 [11] and the activation of the MAP kinases p38, JNK and ERK [12][13][14].Lipid rafts are detergent-resistant plasma membrane microdomains that are enriched in cholesterol and sphingolipids. Being 2358scaffolds of many signaling effectors including lipid-anchored proteins (such as Thy-1 and alkaline phosphatase) and signaling molecules (such as some Src kinase family members), lipid rafts act as platforms to initiate and regulate signal transduction processes in many cellular models [15,16]. Engagement of CD40 molecules leads to CD40 clustering into ceramide-enriched lipid rafts of living human B cells [17,18]. Common early events following CD40 clustering in mouse B cells [19] and in human dendritic cells [20] include Lyn act...

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TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling.

Cited by 321 publications

References 53 publications

Signalling by CD95 and TNF receptors: Not only life and death

Signalling by CD95 and TNF receptors: Not only life and death

MyD genes in negative growth control

CD40 translocation to lipid rafts: Signaling requirements and downstream biological events

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