Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 715

Canonical NF κ B Pathway

The canonical NF κ B pathway is activated by monokines, such as TNF α and

interleukin-1, as well as angiotensin-2. The NF B canonical pathway is associated

with the IKK signalosome composed of 2 homologous protein Ser/Thr kinases —
IKK

κ

α and IKK β — and regulatory IKK γ subunit. The latter binds ubiquitinated

adaptors, recruits the I B for nuclear translocation.

In the cytosol, the active IKK signalosome phosphorylates I

κ B α inhibitor, and liberates NF κ

(Ser32 and
Ser36) that then undergoes proteolysis. The canonical pathway controls the nuclear
translocation primarily of NF

κ B α

B1-RelA heterodimer.
Activated B-cell receptors of B lymphocytes provoke the formation of a
plasmalemmal signalosome that contains scaffold BCL10, paracaspase scaffold
mucosa-associated

κ

lymphoid tissue lymphoma translocation gene product

MALT1, I κ B kinase, and the I κ B-NF κ B (Rel) complex ( BCL10-MALT1-NF κ B

signalosome )[ 1461 ]. Kinase I κ B phosphorylates I κ B inhibitor that is then

degraded, hence allowing NF κ B nuclear import.

The activation of the I κ B kinase complex requires phosphorylation of catalytic

subunits IKK α and IKK β and additional ubiquitination of regulatory subunit

IKK γ . Plasmalemmal scaffold CARMA1 regulates IKK γ ubiquitination, whereas

activated MAP3K7 phosphorylates IKK α and IKK β when T-cell receptor is

stimulated [ 1462 ].
Angiotensin-2 also activates the canonical pathway via its high-affinity re-
ceptor AT 1A and the CARMA3-BCL10-MALT1 complex ( CBM signalosome ;
Sect. 11.5.6.7 )[ 1446 ] . The canonical pathway triggered by angiotensin-2 thus
differs from that primed by TNF

α .

Non-Canonical NF κ B Pathway

The non-canonical pathway is activated by diverse signals, such as TNFSF3,
platelet-derived TNFSF5, TNFSF13b, and viral RNA. The non-canonical pathway
activates the P100 precursor into its mature DNA-binding NF κ B2 form via phos-

phorylation by IKK α , itself phosphorylated (stimulated) by NF κ B-inducing kinase

(NIK or MAP3K14).
In unstimulated cells, MAP3K14 binds a ubiquitin ligase complex made of
TRAF2, TRAF3, and cIAP for constitutive degradation. Activators induce TRAF3
degradation, thereby stabilizing MAP3K14 and causing its oligomerization and
auto-activation. Hence, the non-canonical pathway frees RelA-NF κ B2 and RelB-

NF B1 complexes. The latter selectively controls genes that produce CCL19,

CXCL12, and TNFSF13b that are involved in lymph node organogenesis and
immunity [ 1446 ].

κ