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Apoptosis and survival APRIL and BAFF signaling

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Apoptosis and survival APRIL and BAFF signaling

APRIL and BAFF signaling

Tumor necrosis factor (ligand) superfamily members 13 and 13b ( APRIL andBAFF ) and their receptors - Tumor necrosis factor receptor superfamily members13C, 17 and 13B ( BAFF-R, BCMA and TACI ) - play important roles inthe B-cell and T-cell arms of the immune system [1], [2].BAFF bands to all three receptors BAFF-R, BCMA and TACI,whereas APRIL bands to two of them - BCMA and TACI [3].

One of the most important APRIL/ BAFF -induced mechanisms is anactivation of Nuclear factors of kappa light polypeptide in B-cells (NF-kB) signalingcascades. Activation and nuclear translocation of NF-kB proteins can occur by one of twopathways: canonical and non-canonical.

Activation of non-canonical NF-kB pathway happens upon BAFF activation ofBCMA, TACI and BAFF-R. BCMA and TACI activate TNFreceptor-associated factors 2 and 5 ( TRAF2 and TRAF5 ). These TRAFstransit signal to Mitogen-activated protein kinase kinase kinase 14 ( NIK ) [4], [5], [1].

The exact mechanism of BAFF-R -dependent signaling is unknown, but it isbelieved, that BAFF-R may repress action of TNF receptor-associated factor 3 (TRAF3 ) - inhibitor of TRAF2 and NIK [3]. Then, theactivated NIK phosphorylates Conserved helix-loop-helix ubiquitous kinase (IKK-alpha ), which induces processing of transcription factor NF-kB2 (p100)to NF-kB2(p52) [5], [1].

NF-kB2(p52), along with v-rel reticuloendotheliosis viral oncogene homolog B (RelB ), may activate transcription of B-cell CLL/lymphoma 2 ( Bcl-2 )and/or BCL2-like 1 ( Bcl-XL ), thus stimulating cell survival [5]. Inaddition, RelB may participate in BAFF-R -dependent production ofImmunoglobulins in the earliest stages of B-cell maturation [6]. It isshown, that NF-kB2(p52) may activate transcription of BAFF forming positivefeedback loop [7].

APRIL/ BAFF -induced activation of canonical NF-kB pathway is realizedvia TNF receptor-associated factor 6 ( TRAF6 ). TRAF6 activates theInhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma ( IKKgamma )/ IKK alpha/ IKK beta complex, which subsequentlyphosphorylates NF-kB inhibitor ( I-kB ). Phosphorylation of I-kB leads toits ubiquitination and degradation. Degradation of I-kB liberates transcriptionfactor NF-kB1(p50) and v-rel reticuloendotheliosis viral oncogene homolog A (RelA(p65) ), allowing its rapid translocation from the cytoplasm into thenucleus.

These transcription factors in the form of homo- and heterodimers activatetranscription of anti-apoptotic genes Bcl-XL and BCL2-related protein A1 (BFL1 ) [8]. It is possible that NF-kB1(p50) andRelA(p65) may activate transcription of inflammation proteins Chemokine ligand 4 (MIP-1 beta ), Interleukin 10 ( IL-10 ) [9] andProstaglandin-endoperoxide synthase 2 ( COX-2 ) in TACI -dependent manner[10], [11]. Moreover, these transcription factors may participatein BAFF -dependent stimulation of Fc fragment of IgE low affinity II receptor (CD23 ) and Complement component receptor 2 ( CD1 ) transcription [12], [13], [14]. It is shown, that NF-kB1(p50) andRelA(p65) may activate transcription of BAFF forming a positive feedbackloop [7].

In addition, NF-kB1 (p50) may participate in BAFF-R -dependentproduction of Ig in the B-cell maturation [8].

TACI activates another signal, different from NF-kB pathway, which is theactivation of Nuclear factors of activated T-cells cytoplasmic calcineurin-dependent 2and 1 ( NF-AT1(NFATC2) and NF-AT2(NFATC1) ). It is supposed, thatTACI activates Calcium modulating ligand ( CAML )/ Peptidylprolylisomerase B ( Cyclophilin B )/ Catalytic (A) subunit isoforms of calcineurin (Calcineurin A (catalytic)) cascade [15], [16].NF-AT1(NFATC2) and NF-AT2(NFATC1) may activate transcription of BAFFforming a positive feedback loop [7]. In addition, these transcriptionfactors may participate in TACI -dependent stimulation of COX-2transcription [17], [10].

BCMA and/ TACI may activate Mitogen-activated protein kinase kinasekinase 1 ( MEKK1 )/ Mitogen-activated protein kinase kinase 4 ( MEK4 )/mitogen-activated protein kinase JNK cascade, which may participate, for instance,in antigen presentation and other processes B cell maturation [18], [19].