Pathway Map Details

Apoptosis and survival_APRIL and BAFF signaling

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NF-kB p50/p50, COX-2, MIP-1-beta, NIK(MAP3K14), TRAF6, CD21, NF-AT2(NFATC1), RelA (p65), MEKK1(MAP3K1), NF-kB2 (p52), APRIL(TNFSF13), NF-AT1(NFATC2), BAFF-R, IKK-alpha, Bcl-XL, Calcineurin A (catalytic), TRAF3, IKK-gamma, CAML, TRAF5, NF-kB p50/p65, IKK-beta, BFL1, NF-kB1, IKK (cat), BAFF(TNFSF13B), IL-10, Cyclophilin B, MEK4(MAP2K4), CD23, BCMA(TNFRSF17), JNK(MAPK8-10), NF-kB2 (p100), Bcl-2, TACI(TNFRSF13B), RelB, TRAF2, I-kB


APRIL and BAFF signaling

Tumor necrosis factor (ligand) superfamily members 13 and 13b ( APRIL and BAFF ) and their receptors - Tumor necrosis factor receptor superfamily members 13C, 17 and 13B ( BAFF-R, BCMA and TACI ) - play important roles in the 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 an activation of Nuclear factors of kappa light polypeptide in B-cells (NF-kB) signaling cascades. Activation and nuclear translocation of NF-kB proteins can occur by one of two pathways: canonical and non-canonical.

Activation of non-canonical NF-kB pathway happens upon BAFF activation of BCMA, TACI and BAFF-R. BCMA and TACI activate TNF receptor-associated factors 2 and 5 ( TRAF2 and TRAF5 ). These TRAFs transit 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 is believed, that BAFF-R may repress action of TNF receptor-associated factor 3 ( TRAF3 ) - inhibitor of TRAF2 and NIK [3]. Then, the activated 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]. In addition, RelB may participate in BAFF-R -dependent production of Immunoglobulins in the earliest stages of B-cell maturation [6]. It is shown, that NF-kB2(p52) may activate transcription of BAFF forming positive feedback loop [7].

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

These transcription factors in the form of homo- and heterodimers activate transcription of anti-apoptotic genes Bcl-XL and BCL2-related protein A1 ( BFL1 ) [8]. It is possible that NF-kB1(p50) and RelA(p65) may activate transcription of inflammation proteins Chemokine ligand 4 ( MIP-1 beta ), Interleukin 10 ( IL-10 ) [9] and Prostaglandin-endoperoxide synthase 2 ( COX-2 ) in TACI -dependent manner [10], [11]. Moreover, these transcription factors may participate in 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) and RelA(p65) may activate transcription of BAFF forming a positive feedback loop [7].

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

TACI activates another signal, different from NF-kB pathway, which is the activation of Nuclear factors of activated T-cells cytoplasmic calcineurin-dependent 2 and 1 ( NF-AT1(NFATC2) and NF-AT2(NFATC1) ). It is supposed, that TACI activates Calcium modulating ligand ( CAML )/ Peptidylprolyl isomerase 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 BAFF forming a positive feedback loop [7]. In addition, these transcription factors may participate in TACI -dependent stimulation of COX-2 transcription [17], [10].

BCMA and/ TACI may activate Mitogen-activated protein kinase kinase kinase 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].


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