Monday, March 18, 2013

Signal Transduction Pathway - NF-κB Signaling

NF-κB is another example of signaling pathway where there is direct targeting of a specific family of transcription factors. NF-κB stands for nuclear factor kappa beta. It is a transcription factor that plays an important role in the immune systems and in inflammation as well as in the regulation of proliferation and survival of various animal cells. In response to ligation of many receptors, NF-κB is known to regulate the expression of various cytokines, cyclo-oxygenase (COX-2), growth factors, inhibitors of apoptosis etc.


The activation of NF-κB is mainly by two signaling pathways - the canonical pathway (which is the classical pathway) and the non-canonical pathway (which is also called the alternative pathway). Lets discuss about each of the pathway in detail. But before going ahead, it is important to note the common regulatory step of both the cascades is the activation of IκBkinase (IKK) complex. In unstimulated cells, the inhibitor, NF-κB proteins are bound to IκB protein that maintains NF-κB in an inactive state. Hence, when IκB is activated i.e.; phosphorylated, it gets ubiquitinated and is degraded by proteasome. The IKK complex consists of kinase subunits that are catalytic (IKKα and/or IKKβ) and non-enzymatic protein that is regulatory in nature - known as NEMO which stands for NF-κB essential modulator, also known as IKKγ.

Canonical NF-κB Pathway:
The ligand binds to a cell surface receptor such as the members of the Toll-like receptor superfamily. This binding leads to the recruitment of adapters (such as TRAF) to the cytoplasmic domain of the receptor. These adapters then recruit the IKK complex which comprises of IKKα and/or IKKβ and NEMO or IKKγ subunits. The IKK complex then phosphorylates and consequently degrades IκB inhibitor by ubiquitination. NF-κB translocates to the nucleus to activate the target genes. The canonical pathway activates NF-κB dimers that comprises of Rel-A, c-Rel, RelB and p50.


Non-canonical NF-κB Pathway:
The non-canonical pathway is another arm of NF-κB pathway that predominantly targets the activation of p100/RelB complexes that occurs during the development of lymphoid organs which are responsible for the generation of B and T lymphocytes. The stimuli that activate NF-κB via this pathway are very few which includes lymphotoxin B and b-cell activating factor (BAFF). Note that this pathway does not utilize NEMO/IKKγ.  Here, the ligand binding activates the NF-κB-inducing kinase (NIK). This NIK phosphorylates and activates IKK complex (IKKα and IKKβ complex) which in turn phosphorylates p100. This leads to the liberation of p52/RelB heterodimer. This heterodimer then translocates to nucleus to activate the target genes.
Here ends the explanation of this pathway. Any doubts are welcome!