Classical and Alternative NF-kappaB Pathways

This animation reviews the classical and alternative NF-kappaB pathways that can be targeted for inhibition. It was presented at an independent satellite symposium "Expert Perspectives in Individualized Treatment of Hematologic Malignancies" at the 2010 ASCO meeting in Chicago, Illinois.

Scenes Description.

Scene 1: In the classical pathway, incoming stimuli to cell surface receptors initiate a cytoplasmic cascade, beginning with the activation of the IKK-gamma/IKK-alpha/IKK-beta complex.

IKK-beta becomes phosphorylated.

Scene 2: The IKK complex phosphorylates the IkappaB that is bound to the p50/p65 subunits of NF-kappaB and inhibits its activity.

Scene3: Phosphorylated IkappaB undergoes ubiquitinylation followed by proteasomal degradation. This permits NF-kappaB translocation to the nucleus, leading to gene transcription of anti-apoptotic and inflammatory proteins.

Scene 4: Bortezomib inhibits proteasomes, preventing the degradation of IkappaB, thereby indirectly inhibiting NF-kappaB transcription activity.

Scene 5: In the alternative pathway, extracellular stimuli stimulate cell surface receptors, which leads to the activation of NIK.

Scene 6: NIK phosphorylates dimerized IKK-alpha.

Scene 7: The RelB/p100 complex is phosphorylated by the IKK-alpha dimer.

Scene 8: Upon ubiquitinylation, p100 is cleaved. This yields a RelB/p52 complex which translocates to the nucleus to transcribe proteins related to lymphoid organ development and homeostasis.